Compounds which potentiate AMPA receptor and uses thereof in medicine

ABSTRACT

Compounds of formula (I) and salts are provided:  
                 
along with pharmaceutical compositions, uses in medicine, e.g., treating disease or condition mediated by a reduction or imbalance in glutamate receptor function, such as schizophrenia or cognition impairment.

This invention relates to novel compounds which potentiate the glutamatereceptor. The invention also relates to the use of the compounds intreating diseases and conditions mediated by potentiation of theglutamate receptor, compositions containing the derivatives andprocesses for their preparation.

Glutamate receptors, which mediate the majority of fast excitatoryneurotransmission in the mammalian central nervous system (CNS), areactivated by the excitatory amino acid, L-glutamate (for review seeWatkins J C, Krogsgaard-Larsen P, Honore T (1990) Trends Pharmacol Sci11: 25-33).

Glutamate receptors can be divided into two distinct families. TheG-protein or second messenger-linked “metabotropic” glutamate receptorfamily which can be subdivided into three groups (Group I, mGlu1 andmGlu5; Group II, mGlu2 and mGlu3; Group III, mGlu4, mGlu6, mGlu7, mGlu8)based on sequence homology and intracellular transduction mechanisms(for review see Conn P J and Pinn J P (1997) Ann Rev Pharmacol Toxicol37: 205-237). The “ionotropic” glutamate receptor family, which directlycouple to ligand-gated cation channels, can be subdivided into at leastthree subtypes based on depolarizing activation by selective agonists,N-methyl-D-aspartate (NMDA),α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainicacid (KA) (for review see Dingledine R, Borges K, Bowie, Traynelis S(1999) 51: 7-61).

Native AMPA receptors (AMPAR) exist as heterotetramers consisting ofcombinations of four different protein subunits (GluR1-4) (for reviewsee Bettler B and Muller C (1995) 34: 123-139.). Receptor subunitdiversity is increased further as each subunit can undergo alternativesplicing of a 38 amino acid sequence in the extracellular region justbefore the fourth membrane spanning domain M4. Such editing results inso-called ‘flip’ and ‘flop’ receptor isoforms which differ in kineticand pharmacological properties (Sommer B, Keinanen K, Verdoon T A,Wisden W, Burnashev N, Herb A, Kohler M, Takagi T, Sakmann B, Seeburg PH (1990) Science 249: 1580-1585).

Additionally, post-transcriptional editing of GluR2 mRNA changes aneutral glutamine to a positively charged arginine within M2. In normalhumans >99% GluR2 is edited in this way. AMPAR containing such editedGluR2 subunit exhibit low calcium permeability (Burnachev N, Monyer H,Seeburg P H, Sakmann B (1992) Neuron 8: 189-198). There is a suggestion,however, that the number of AMPAR with high calcium permeability iselevated in certain disease-associated conditions (Weiss J H, and SensiS L (2000) Trends in Neurosci 23: 365-371).

AMPAR depolarization removes voltage dependent Mg²⁺ block of NMDAreceptors which in turn leads to NMDA receptor activation, an integralstage in the induction of Long Term Potentiation (“LTP”) (Bliss T V P,Collingridge G L (1993) Nature 361: 31-9). LTP is a physiologicalmeasure of increased synaptic strength following a repetitive stimulusor activity, such as occurs during learning.

It has been reported that direct activation of glutamate receptors byagonists, in conditions where glutamate receptor function is reduced,increases the risk of excitotoxicity and additional neuronal damage.AMPAR positive allosteric modulators do not activate the receptordirectly. However, when the ligand (L-glutamate or AMPA) is presentAMPAR modulators increase receptor activity. Thus, AMPA receptormodulators enhance synaptic function when glutamate is released and isable to bind at post-synaptic receptor sites.

Compounds which act as AMPAR positive allosteric modulators have beenshown to increase ligand affinity for the receptor (Arai A, Guidotti A,Costa E, Lynch G (1996) Neuroreport. 7: 2211-5.); reduce receptordesensitization and reduce receptor deactivation (Arai A C, Kessler M,Rogers G, Lynch G (2000) 58: 802-813) and facilitate the induction ofLTP both in vitro (Arai A, Guidotti A, Costa E, Lynch G (1996) 7:2211-5.) and in vivo (Staubli U, Perez Y, Xu F, Rogers G, Ingvar M,Stone-Elander S, Lynch G (1994) Proc Natl Acad Sci 91: 11158-11162).Such compounds also enhance the learning and performance of variouscognitive tasks in rodent (Zivkovic I, Thompson D M, Bertolino M, UzunovD, DiBella M, Costa E, Guidotti A (1995) JPET 272: 300-309, Lebrun C,Pilliere E, Lestage P (2000) Eu J Pharmacol 401: 205-212), sub-humanprimate (Thompson D M, Guidotti A, DiBella M, Costa E (1995) Proc NatlAcad Sci 92: 7667-7671) and man (Ingvar M, Ambros-Ingerson J, Davis M,Granger R, Kessler M, Rogers G A, Schehr R S, Lynch G (1997) Exp Neurol146: 553-559). The efficacy of various AMPAR positive allostericmodulators in pre-clinical and clinical models of psychiatric disorders,such as schizophrenia, have been investigated (Morrow J A, Maclean J KF, Jamieson C (2006) Current Opinion in Drug Discovery and Development9(5) 571-579)

Compounds which act as AMPAR positive allosteric modulators are known,for example in international patent application WO2006/015828.JP2001-22-390 discloses the compound4-methyl-N-[4-[4,5,6,7-tetrahydro-3-(trifluoromethyl)-1H-indazol-1-yl]phenyl]-1,2,3-thiadiazole-5-carboxamideand salts thereof as a calcium channel inhibitor. We have discoverednovel compounds which potentiate the AMPA receptor.

In the first aspect, the present invention provides a compound offormula (I), or a salt, or solvate thereof:

wherein:

-   -   q is 0 or 1;    -   n is 0, 1, or 2;    -   X is CR⁶R⁷, where R⁶ and R⁷ are each independently selected from        the group consisting of hydrogen, methyl and fluoro, but R⁶ and        R⁷ are not both simultaneously methyl; or, when n is 1, R⁶ and        R⁷ together with the carbon atom to which they are attached,        form a 3-membered carbocyclic ring;    -   Y is selected from the group consisting of CO, NR⁸CO, SO, SO₂        and NR⁸SO₂;    -   R⁸ is selected from the group consisting of hydrogen, C₁₋₄ alkyl        and C₂₋₄alkenyl;    -   m is 0 or 1; and    -   a) when n is 0 and m=1, then R¹ is selected from the group        consisting of (i) C₁₋₄alkyl, (ii) a C-linked 5-membered aromatic        heterocyclic group optionally substituted with methyl, (iii)        NHR² and (iv) NR^(2′)R³, wherein:        -   R² is selected from the group consisting of C₁₋₆straight            chain alkyl, C₄₋₆branched chain alkyl and a group            —(CH₂)_(p)Z wherein p is 1, 2 or 3;        -   Z is hydroxy, methoxy, NHMe, phenyl or a 5- or 6-membered            non-aromatic heterocyclic group, the phenyl or heterocyclic            group being optionally substituted by one, two or three            groups independently selected from the group consisting of            halo, C₁₋₄alkyl and haloC₁₋₄alkyl; wherein when Y is CO, R²            is not (CH₂)₂pyrrolidinyl;        -   R^(2′) is selected from the group consisting of methyl and            ethyl;        -   R³ is selected from the group consisting of C₁₋₆alkyl and a            group —(CH₂)_(p)Z′ wherein p is 1, 2 or 3;        -   Z′ is hydroxy, methoxy, NHMe, phenyl or a 5- or 6-membered            non-aromatic or aromatic heterocyclic group, the phenyl or            heterocyclic group being optionally substituted by one, two            or three groups independently selected from the group            consisting of halo, C₁₋₄alkyl and haloC₁₋₄alkyl; or        -   R^(2′) and R³, together with the nitrogen atom to which they            are attached, form:            -   (i) a 4 or 5-membered non-aromatic heterocyclic group,                which ring is optionally substituted by one, two or                three groups independently selected from the group                consisting of halo, hydroxy, NR¹³R¹⁴ (wherein R¹³ and                R¹⁴ are independently selected from the group consisting                of hydrogen and C₁₋₄alkyl), haloC₁₋₄alkyl, and keto; or            -   (ii) a 6-membered non-aromatic heterocyclic group, which                ring is optionally substituted by one, two or three                groups independently selected from the group consisting                of halo, hydroxy, NR¹³R¹⁴ (wherein R¹³ and R¹⁴ are                independently selected from the group consisting of                hydrogen and C₁₋₄alkyl), C₂₋₄alkyl, haloC₁₋₄alkyl and                keto;    -   b) when n and m are both simultaneously 0, R¹ is selected from        the group consisting of:        -   C₁₋₆alkoxy;        -   a monocyclic saturated or partially unsaturated 5- or            6-membered heterocyclic group, attached through a carbon            atom and optionally substituted by one, two or three groups            independently selected from the group consisting of            C₁₋₄alkyl, C(O)C₁₋₄alkyl, haloC₁₋₄alkyl, halo and keto;        -   N-linked pyrrolidinyl, optionally substituted with one, two            or three groups independently selected from the group            consisting of C₁₋₄alkyl, C(O)C₁₋₄alkyl, halo C₁₋₄alkyl, halo            and keto; and        -   oxazolyl or imidazolyl, both being optionally substituted by            C₁₋₄alkyl;    -   c) when n is 1 or 2, and m is 1, R¹ is selected from the group        consisting of C₁₋₄alkyl, benzyl, cyclopropyl, thienyl, and        NR⁹R¹⁰ wherein:        -   R⁹ is selected from the group consisting of hydrogen and            C₁₋₄alkyl, and R¹⁰ is selected from the group consisting of            C₁₋₆ straight chain alkyl, C₃₋₆cycloalkyl and —(CH₂)_(p)Z            wherein p is 1, 2 or 3;        -   Z is a phenyl or a 5- or 6-membered heterocyclic group, the            phenyl or heterocyclic group being optionally substituted by            one, two or three groups independently selected from the            group consisting of halo and C₁₋₄alkyl; or        -   R⁹ and R¹⁰, together with the nitrogen atom to which they            are attached, form a 5-membered aromatic or non-aromatic            heterocyclic group or a 6-membered non-aromatic heterocyclic            group, any of the rings being optionally substituted by one,            two or three groups independently selected from the group            consisting of C₁₋₄alkyl, halo, phenyl and (in the case of a            non-aromatic ring) keto; and    -   d) when n is 1 or 2, and m is 0, R¹ is selected from the group        consisting of cyano, hydroxy, NH₂, a C-linked 5-membered        aromatic heterocyclic group optionally substituted with one, two        or three groups independently selected from the group consisting        of C₁₋₆alkyl and C₃₋₆cycloalkyl, and NR¹¹R¹² in which:        -   R¹¹ is hydrogen and R¹² is selected from the group            consisting of SO₂C₁₋₄alkyl, SO₂C₃₋₆cycloalkyl,            C(O)C₁₋₄alkyl, and C(O)C₂₋₄alkenyl; or R¹¹ is selected from            the group consisting of C₁₋₄alkyl and C₂₋₄alkenyl, and R¹²            is selected from the group consisting of SO₂C₁₋₄alkyl,            SO₂C₃₋₆cycloalkyl, C(O)C₁₋₄alkyl, C(O)phenyl and            C(O)C₂₋₄alkenyl or        -   R¹¹ and R¹², together with the nitrogen atom to which they            are attached, form a group selected from the group            consisting of:            -   (i) a 5-membered aromatic heterocyclic group which is                optionally substituted by one or two groups                independently selected from the group consisting of                C₁₋₄alkyl, halo, haloC₁₋₄alkyl, hydroxy, C₃₋₆cycloalkyl                and C₁₋₄alkoxy; and            -   (ii) imidazolyl substituted by phenyl;            -   (iii) a 5-membered non-aromatic heterocyclic group which                is substituted by one, two or three groups independently                selected from the group consisting of keto, hydroxy and                C₁₋₄alkoxy; and            -   (iv) a 6-membered non-aromatic heterocyclic group, which                is optionally substituted by one, two or three groups                independently selected from the group consisting of                keto, hydroxy and C₁₋₄alkoxy;    -   excluding        4-methyl-N-[4-[4,5,6,7-tetrahydro-3-(trifluoromethyl)-1H-indazol-1-yl]phenyl]-1,2,3-thiadiazole-5-carboxamide        and salts thereof.

The term “halo” refers to fluoro, chloro, bromo or iodo.

The term “C₁₋₆alkyl” refers to an alkyl group having from one to sixcarbon atoms; and the term “C₁₋₄alkyl” refers to an alkyl group havingfrom one to four carbon atoms. Unless otherwise indicated, C₁₋₄alkyl orC₁₋₆alkyl may be a straight chain or branched alkyl group. For example,a C₁₋₄alkyl group may be selected from the group consisting of methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl. A C₁₋₆alkylgroup may be selected from the group consisting of a C₁₋₄alkyl group,sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl. For example,C₁₋₄alkyl is methyl. The term “C₁₋₆ straight chain alkyl” means that theC₁₋₆alkyl group is in a straight chain, for example methyl, ethyl,propyl, butyl, pentyl and hexyl. The term “C₄₋₆ branched chain alkyl”means that the C₄₋₆alkyl group is in a branched chain, for examplet-butyl. “Me” means methyl. “Et” means ethyl.

“Ph” means phenyl.

The term “C₁₋₄alkoxy” refers to the group —O—C₁₋₄alkyl wherein C₁₋₄alkylis as defined above.

The term “C₂₋₄alkenyl” herein refers to a linear or branched hydrocarbongroup containing one or more carbon-carbon double bonds and having from2 to 4 carbon atoms. Examples of such groups include ethenyl, propenyland butenyl.

The term “C₃₋₆cycloalkyl” refers to a cycloalkyl group consisting offrom 3 to 6 carbon atoms, ie cyclopropanyl, cyclobutanyl, cyclopentanyland cyclohexanyl.

The term “haloC₁₋₄alkyl” refers to a C₁₋₄alkyl group as defined abovewhich is substituted with any number of fluorine, chlorine, bromine, oriodine atoms, including with mixtures of those atoms. A haloC₁₋₄alkylgroup may, for example contain 1, 2 or 3 halogen atoms. For example, ahaloC₁₋₄alkyl group may have all hydrogen atoms replaced with halogenatoms. Examples of haloC₁₋₄alkyl groups include fluoromethyl,difluoromethyl and trifluoromethyl.

The term “3-membered carbocyclic ring” as it appears in the definitionof R⁶ and R⁷, refers to the following group formed by R⁶ and R⁷:

The term “C-linked 5-membered aromatic heterocyclic group” as it appearsin the definition of R¹ when n is 0 and m is 1 refers to a C-linkedaromatic heterocyclic group which contains one, two or three heteroatomsselected from the group consisting of nitrogen, oxygen and sulphur.Examples include pyrrolyl, pyrrolinyl, pyrazolinyl, oxazolyl, isoxazoyl,imidazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, isothiazolyl,thiazolyl, triazolyl, furyl and thienyl.

The terms “non-aromatic 5- or 6-membered heterocyclic group” and“aromatic or non-aromatic 5- or 6-membered heterocyclic group” as itappears in the definition of Z and Z′ refer to an aromatic ornon-aromatic 5- or 6-membered group which contains one, two or threeheteroatoms independently selected from the group consisting ofnitrogen, oxygen and sulfur. Examples of aromatic groups include:pyrrolyl, pyrazolinyl, oxazolyl, isoxazoyl, imidazolyl, pyrazolyl,thiadiazolyl, oxadiazolyl, isothiazolyl, thiazolyl, triazolyl, furyl,thienyl, pyridyl, thiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl andtriazinyl. Examples of non-aromatic groups include pyrrolidinyl,pyrrolinyl, imidazolidinyl, pyrazolidinyl, isothiazolyl, thiazolyl,tetrahydrofuranyl, dioxolanyl, piperidyl, piperazinyl, morpholinyl,thiomorpholinyl, tetrahydrothienyl, dioxanyl and dithianyl.

The term “4 or 5-membered non-aromatic heterocyclic group”, as itappears in the definition of R² and R³, refers to a 4- or 5-memberednon-aromatic ring formed by R² and R³, together with the nitrogen towhich R² and R³ are attached, which ring may contain one, two or threeadditional heteroatoms independently selected from the group consistingof nitrogen, oxygen and sulfur. Examples include azetidinyl,pyrrolidinyl imidazolidinyl, pyrazolidinyl, isothiazolyl and thiazolyl.

The term “6-membered non-aromatic heterocyclic group”, as it appears inthe definition of R² and R³, refers to a 6-membered non-aromatic ringformed by R² and R³, together with the nitrogen to which R^(2′) and R³are attached, which ring may contain one, two or three additionalheteroatoms independently selected from the group consisting ofnitrogen, oxygen and sulfur. Examples include morpholinyl,thiomorpholinyl, piperidinyl and piperazinyl.

“CO” and “C(═O)” are interchangeable and represent a carbonyl group. Theterm “keto” refers to the group ═O.

The term “monocyclic saturated or partially unsaturated 5- or 6-memberedheterocyclic group, attached through a carbon atom”, as it appears inthe definition of R¹ when n and m are both 0, refers to a 5- or6-membered ring which is attached through a carbon atom and whichcontains one, two or three heteroatoms independently selected from thegroup consisting of nitrogen, oxygen and sulfur. Examples includepyrrolidinyl, pyrrolinyl, imidazolinyl, imidazolidinyl, piperidyl andmorpholinyl.

The term “5-membered aromatic or non-aromatic heterocyclic group”, as itappears in the definition of R⁹ and R¹⁰, refers to a 5-membered aromaticring or a 5-membered non-aromatic ring, formed by R⁹ and R¹⁰, togetherwith the nitrogen to which R⁹ and R¹⁰ are attached, which ring mayinclude one, two or three further heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulphur. In one embodiment, theheterocyclic group contains zero, one or two further heteroatomsselected from the group consisting of nitrogen, oxygen and sulphur.Examples include pyrrolidinyl, imidazolidinyl, pyrazolidinyl,isothiazolyl, thiazolyl, pyrrolyl, pyrazolinyl, isoxazoyl, imidazolyl,pyrazolyl, thiadiazolyl, oxadiazolyl, isothiazolyl, thiazolyl andtriazolyl.

The term “6-membered non-aromatic heterocyclic group” as it appears inthe definition of R⁹ and R¹⁰, refers to a 6-membered non-aromatic ring,formed by R⁹ and R¹⁰, together with the nitrogen to which R⁹ and R¹⁰ areattached, which ring may include one or more further heteroatomsselected from the group consisting of nitrogen, oxygen and sulphur. Inone embodiment, the heterocyclic group contains zero, one, two or threefurther heteroatoms selected from the group consisting of nitrogen,oxygen and sulphur. Examples include piperidyl, piperazinyl, morpholinyland thiomorpholinyl.

The term “C-linked 5-membered aromatic heterocyclic group” as it appearsin the definition of R¹ when n is 1 or 2 and m is 0, refers to aC-linked aromatic heterocyclic group which contains one, two or threeheteroatoms selected from the group consisting of nitrogen, oxygen andsulphur. Examples include pyrrolyl, pyrrolinyl, pyrazolinyl, oxazolyl,isoxazoyl, imidazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl,isothiazolyl, thiazolyl, triazolyl, furyl and thienyl.

The term “5-membered aromatic heterocyclic group” as it appears in thedefinition of R¹¹ and R¹² when n is 1 or 2, m is 0, and R¹ is NR¹¹R¹²,refers to a 5-membered aromatic heterocyclic group, formed by R¹⁰ andR¹¹, together with the nitrogen to which R¹⁰ and R¹¹ are attached, whichring may contain one, two or three further heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulphur. Examples includepyrrolyl, pyrrolinyl, pyrazolinyl, oxazolyl, isoxazoyl, imidazolyl,pyrazolyl, thiadiazolyl, oxadiazolyl, isothiazolyl, thiazolyl andtriazolyl.

The term “5-membered non-aromatic heterocyclic group” as it appears inthe definition of R¹¹ and R¹² when n is 1 or 2, m is 0, and R¹ isNR¹¹R¹², refers to a 5-membered non-aromatic heterocyclic group, formedby R¹⁰ and R¹¹, together with the nitrogen to which R¹⁰ and R¹¹ areattached, which ring may contain one, two or three further heteroatomsselected from the group consisting of nitrogen, oxygen and sulphur.Examples include pyrrolidinyl, thiazolidinyl, imidazolidinyl,pyrazolidinyl and isothiazolidinyl.

The term “6-membered non-aromatic heterocyclic group” as it appears inthe definition of R¹¹ and R¹² when n is 1 or 2, m is 0, and R¹ isNR¹¹R¹², refers to a 6-membered non-aromatic heterocyclic group, formedby R¹⁰ and R¹¹, together with the nitrogen to which R¹⁰ and R¹¹ areattached, which ring may contain one, two or three further heteroatomsselected from the group consisting of nitrogen, oxygen and sulphur.Examples include piperidyl, piperazinyl, morpholinyl andthiomorpholinyl.

Examples of compounds of formula (I) include

-   1.    N,N-dimethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 1)-   2.    1-[4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 2)-   3.    N-methyl-N-(phenylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 3)-   4.    N-ethyl-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 4)-   5.    N-butyl-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 5)-   6.    N-methyl-N-(2-phenylethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 6)-   7.    N,N-dimethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide    (Example 7)-   8.    1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}ethanone    (Example 8)-   9.    1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-1-propanone    (Example 9)-   10.    1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 10)-   11.    1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-2-propanone    (Example 11)-   12.    N,N-dimethyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 12)-   13.    1-{4-[2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 13)-   14.    N-ethyl-N-methyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 14)-   15.    N-methyl-N-(phenylmethyl)-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 15)-   16.    N-butyl-N-methyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 16)-   17.    N-methyl-N-(2-phenylethyl)-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 17)-   18.    1-{[4-(1-pyrrolidinylcarbonyl)phenyl]methyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 18)-   19.    1-{4-[1-methyl-2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 19)-   20.    N,N-dimethyl-3-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}propanamide    (Example 20)-   21.    1-{4-[3-oxo-3-(1-pyrrolidinyl)propyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 21)-   22.    1-{4-[1-(1-pyrrolidinylcarbonyl)cyclopropyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 22)-   23.    1-{4-[2-oxo-2-(1-piperidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 23)-   24.    1-{4-[2-(3,3-difluoro-1-pyrrolidinyl)-2-oxoethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 24)-   25.    N-methyl-N-propyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 25)-   26.    N-cyclopentyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 26)-   27.    N-methyl-N-(2-thienylmethyl)-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 27)-   28.    {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetonitrile    (Example 28)-   29.    {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanol    (Example 29)-   30.    N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide    (Example 30)-   31.    1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-pyrrolidinone    (Example 31)-   32.    N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)propanamide    (Example 32)-   33.    N-ethyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide    (Example 33)-   34.    1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-piperidinone    (Example 34)-   35.    1-methyl-5-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-2-pyrrolidinone    (Example 35)-   36.    N-[3-(1H-imidazol-1-yl)propyl]-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 36)-   37.    N-methyl-N-[2-(2-thienyl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 37)-   38.    N-methyl-N-[2-(1H-1,2,4-triazol-1-yl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 38)-   39.    N-methyl-N-(1,3-thiazol-2-ylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 39)-   40.    N-methyl-N-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 40)-   41.    N-methyl-N-(2-thienylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 41)-   42.    N-methyl-N-(3-pyridinylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 42)-   43.    N-(2-furanylmethyl)-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 43)-   44.    N-[(4-fluorophenyl)methyl]-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 44)-   45.    1-[4-(4-morpholinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 45)-   46.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)methanesulfonamide    (Example 46)-   47.    1-{4-[1-fluoro-2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   48.    1-{4-[1,1-difluoro-2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   49.    N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)methanesulfonamide-   50.    1-(4-{[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]methyl}phenyl)-2-pyrrolidinone-   51.    N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-1-pyrrolidinecarboxamide-   52.    5-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-2-pyrrolidinone-   53.    N-(1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}ethyl)acetamide-   54.    N-methyl-N-(1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}ethyl)acetamide-   55.    1-[4-(1-acetyl-2-pyrrolidinyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   56.    1-(2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}ethyl)-2-pyrrolidinone-   57.    1-{4-[(1,1-dioxido-2-isothiazolidinyl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   58.    2-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)propanamide-   59.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)butanamide-   60.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-thiophenecarboxamide-   61.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)propanamide-   62.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide-   63.    N-methyl-2-phenyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide-   64.    N-(2-hydroxyethyl)-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   65. N-methyl-N-[2-(methyloxy)ethyl]-4-[3-(trifluoro    methyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   66.    N-methyl-N-[2-(methylamino)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   67.    1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}carbonyl)-3-pyrrolidinol-   68.    N-methyl-1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}carbonyl)-3-pyrrolidinamine-   69.    1-[4-(1-azetidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   70.    1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}carbonyl)-3-azetidinol-   71.    (3,3-difluorocyclobutyl){4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanone-   72.    1-[4-(1H-imidazol-1-yl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   73.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propenamide-   74.    N-(1-methylethenyl)-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propenamide-   75.    N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propenamide-   76.    1-{4-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   77.    1-{4-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   78.    N-ethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   79.    N-methyl-N-(1-methylethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   80.    1-[4-(1-piperidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   81.    N,N-diethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   82.    N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   83.    1-{4-[2-oxo-2-(2-phenyl-1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   84.    N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)benzamide-   85.    1-[4-(1,3-oxazol-5-yl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   86.    1-[4-(propyloxy)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   87.    1-[4-(1-methyl-1H-imidazol-4-yl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   88.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propanesulfonamide-   89.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)cyclopropanesulfonamide-   90.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)cyclopentanesulfonamide-   91.    1-[4-(1-pyrrolidinylsulfonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   92.    N-(2-methylpropyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide-   93.    1-[4-(4-morpholinylsulfonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   94.    N-[2-(methyloxy)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide-   95.    N-[2-(1-pyrrolidinyl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide-   96.    N-(tetrahydro-2-furanylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide-   97.    1-[4-(1H-imidazol-1-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   98.    1-[4-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   99.    1-[4-(1H-pyrazol-1-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   100.    1-[4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   101.    1-[4-(2H-1,2,3-triazol-2-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   102.    1-{4-[(4-methyl-1H-pyrazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   103.    1-{4-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   104.    3-(trifluoromethyl)-1-(4-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)-4,5,6,7-tetrahydro-1H-indazole-   105.    3-(trifluoromethyl)-1-(4-{[5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)-4,5,6,7-tetrahydro-1H-indazole-   106.    1-(4-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   107.    1-(4-{[3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   108.    1-{4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   109.    1-(4-{[2-(1-methylethyl)-1H-imidazol-1-yl]methyl}phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   110.    1-{4-[(4-phenyl-1H-imidazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   111.    1-{4-[(4-bromo-1H-pyrazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   112.    N-methyl-1H-imidazol-2-yl){4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanone-   113.    N-methyl-N-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-1-pyrrolidinecarboxamide    and salts and solvates thereof.

In one embodiment, the compound is selected from the group consistingof:

Examples of compounds of formula (I) include

-   N,N-dimethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 1)-   1-[4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 2)-   N-methyl-N-(phenylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 3)-   N-ethyl-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 4)-   N-butyl-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 5)-   N-methyl-N-(2-phenylethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 6)-   N,N-dimethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide    (Example 7)-   1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}ethanone    (Example 8)-   1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-1-propanone    (Example 9)-   1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 10)-   1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-2-propanone    (Example 11)-   N,N-dimethyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 12)-   1-{4-[2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 13)-   N-ethyl-N-methyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 14)-   N-methyl-N-(phenylmethyl)-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 15)-   N-butyl-N-methyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 16)-   N-methyl-N-(2-phenylethyl)-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 17)-   1-{[4-(1-pyrrolidinylcarbonyl)phenyl]methyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 18)-   1-{4-[1-methyl-2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 19)-   N,N-dimethyl-3-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}propanamide    (Example 20)-   1-{4-[3-oxo-3-(1-pyrrolidinyl)propyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 21)-   1-{4-[1-(1-pyrrolidinylcarbonyl)cyclopropyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 22)-   1-{4-[2-oxo-2-(1-piperidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 23)-   1-{4-[2-(3,3-difluoro-1-pyrrolidinyl)-2-oxoethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 24)-   N-methyl-N-propyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 25)-   N-cyclopentyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 26)-   N-methyl-N-(2-thienylmethyl)-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 27)-   {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetonitrile    (Example 28)-   {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanol    (Example 29)-   N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide    (Example 30)-   1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-pyrrolidinone    (Example 31)-   N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)propanamide    (Example 32)-   N-ethyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide    (Example 33)-   1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-piperidinone    (Example 34)-   1-methyl-5-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-2-pyrrolidinone    (Example 35)-   N-[3-(1H-imidazol-1-yl)propyl]-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 36)-   N-methyl-N-[2-(2-thienyl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 37)-   N-methyl-N-[2-(1H-1,2,4-triazol-1-yl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 38)-   N-methyl-N-(1,3-thiazol-2-ylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 39)-   N-methyl-N-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 40)-   N-methyl-N-(2-thienylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 41)-   N-methyl-N-(3-pyridinylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 42)-   N-(2-furanyl    methyl)-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 43) and-   N-[(4-fluorophenyl)methyl]-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 44).

In one embodiment, the compound is selected from the group consistingof:

-   N,N-dimethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 1)-   1-[4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 2)-   N-methyl-N-(phenylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 3)-   N-ethyl-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 4)-   N-butyl-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 5)-   N-methyl-N-(2-phenylethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 6)-   N,N-dimethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide    (Example 7)-   1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}ethanone    (Example 8)-   1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-1-propanone    (Example 9)-   1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 10)-   1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-2-propanone    (Example 11)-   N,N-dimethyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 12)-   1-{4-[2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 13)-   N-ethyl-N-methyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 14)-   N-methyl-N-(phenylmethyl)-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 15)-   N-butyl-N-methyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 16)-   N-methyl-N-(2-phenylethyl)-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 17)-   1-{[4-(1-pyrrolidinylcarbonyl)phenyl]methyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 18)-   1-{4-[1-methyl-2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 19)-   N,N-dimethyl-3-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}propanamide    (Example 20)-   1-{4-[3-oxo-3-(1-pyrrolidinyl)propyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 21)-   1-{4-[1-(1-pyrrolidinylcarbonyl)cyclopropyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 22)-   1-{4-[2-oxo-2-(1-piperidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 23)-   1-{4-[2-(3,3-difluoro-1-pyrrolidinyl)-2-oxoethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 24)-   N-methyl-N-propyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 25)-   N-cyclopentyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 26)-   N-methyl-N-(2-thienylmethyl)-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 27)-   {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetonitrile    (Example 28)-   {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanol    (Example 29)-   N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide    (Example 30)-   1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-pyrrolidinone    (Example 31)-   N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)propanamide    (Example 32)-   N-ethyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide    (Example 33)-   1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-piperidinone    (Example 34)-   1-methyl-5-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-2-pyrrolidinone    (Example 35)-   N-[3-(1H-imidazol-1-yl)propyl]-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 36)-   N-methyl-N-[2-(2-thienyl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 37)-   N-methyl-N-[2-(1H-1,2,4-triazol-1-yl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 38)-   N-methyl-N-(1,3-thiazol-2-ylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 39)-   N-methyl-N-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 40)-   N-methyl-N-(2-thienylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 41)-   N-methyl-N-(3-pyridinylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 42)-   N-(2-furanyl    methyl)-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 43)-   N-[(4-fluorophenyl)methyl]-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 44)-   1-[4-(4-morpholinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 45)-   N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)methanesulfonamide    (Example 46)    and salts and solvates thereof.

In one embodiment, the compound is selected from the group consistingof:

-   1.    1-{4-[1-fluoro-2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   2.    1-{4-[1,1-difluoro-2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   3.    N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)methanesulfonamide-   4.    1-(4-{[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]methyl}phenyl)-2-pyrrolidinone-   5.    N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-1-pyrrolidinecarboxamide-   6.    5-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-2-pyrrolidinone-   7.    N-(1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}ethyl)acetamide-   8.    N-methyl-N-(1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}ethyl)acetamide-   9.    1-[4-(1-acetyl-2-pyrrolidinyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   10.    1-(2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}ethyl)-2-pyrrolidinone-   11.    1-{4-[(1,1-dioxido-2-isothiazolidinyl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   12.    2-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)propanamide-   13.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)butanamide-   14.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-thiophenecarboxamide-   15.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)propanamide-   16.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide-   17.    N-methyl-2-phenyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide-   18.    N-(2-hydroxyethyl)-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   19.    N-methyl-N-[2-(methyloxy)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   20.    N-methyl-N-[2-(methylamino)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   21.    1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}carbonyl)-3-pyrrolidinol-   22.    N-methyl-1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}carbonyl)-3-pyrrolidinamine-   23.    1-[4-(1-azetidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   24.    1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}carbonyl)-3-azetidinol-   25.    (3,3-difluorocyclobutyl){4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanone-   26.    1-[4-(1H-imidazol-1-yl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   27.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propenamide-   28.    N-(1-methylethenyl)-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propenamide-   29.    N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propenamide-   30.    1-{4-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   31.    1-{4-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   32.    N-ethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   33.    N-methyl-N-(1-methylethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   34.    1-[4-(1-piperidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   35.    N,N-diethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   36.    N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   37.    1-{4-[2-oxo-2-(2-phenyl-1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   38.    N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)benzamide-   39.    1-[4-(1,3-oxazol-5-yl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   40.    1-[4-(propyloxy)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   41.    1-[4-(1-methyl-1H-imidazol-4-yl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   42.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propanesulfonamide-   43.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)cyclopropanesulfonamide-   44.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)cyclopentanesulfonamide-   45.    1-[4-(1-pyrrolidinylsulfonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   46.    N-(2-methylpropyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide-   47.    1-[4-(4-morpholinylsulfonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   48.    N-[2-(methyloxy)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide-   49.    N-[2-(1-pyrrolidinyl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide-   50.    N-(tetrahydro-2-furanylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide-   51.    1-[4-(1H-imidazol-1-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   52.    1-[4-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   53.    1-[4-(1H-pyrazol-1-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   54.    1-[4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   55.    1-[4-(2H-1,2,3-triazol-2-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   56.    1-{4-[(4-methyl-1H-pyrazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   57.    1-{4-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   58.    3-(trifluoromethyl)-1-(4-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)-4,5,6,7-tetrahydro-1H-indazole-   59.    3-(trifluoromethyl)-1-(4-{[5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)-4,5,6,7-tetrahydro-1H-indazole-   60.    1-(4-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   61.    1-(4-{[3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   62.    1-{4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   63.    1-(4-{[2-(1-methylethyl)-1H-imidazol-1-yl]methyl}phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   64.    1-{4-[(4-phenyl-1H-imidazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   65.    1-{4-[(4-bromo-1H-pyrazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   66.    N-methyl-1H-imidazol-2-yl){4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanone-   67.    N-methyl-N-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-1-pyrrolidinecarboxamide    and salts and solvates thereof.

The present invention also provides a compound of formula (A), or asalt, or solvate thereof:

wherein:

-   -   q is 0 or 1;    -   n is 0, 1, or 2;    -   X is CR⁶R⁷, where R⁶ and R⁷ are each independently selected from        the group consisting of hydrogen, methyl and fluoro, but R⁶ and        R⁷ are not both simultaneously methyl; or, when n is 1, R⁶ and        R⁷ together with the carbon atom to which they are attached,        form a 3-membered carbocyclic ring;    -   Y is selected from the group consisting of CO, NR⁸CO, SO, SO₂        and NR⁸SO₂;    -   R⁸ is selected from the group consisting of hydrogen,        C₂₋₄alkenyl and C₁₋₄alkyl;    -   m is 0 or 1; and    -   a) when n is 0 and m=1, then R¹ is selected from the group        consisting of (i) C₁₋₄alkyl, (ii) a C-linked 5-membered aromatic        heterocyclic group optionally substituted with methyl, (iii)        NHR² and (iv) NR^(2′)R³, wherein:        -   R² is selected from the group consisting of C₁₋₆straight            chain alkyl, C₄₋₆branched chain alkyl and a group            —(CH₂)_(p)Z wherein p is 1, 2 or 3;        -   Z is hydroxy, methoxy, NHMe, phenyl or a 5- or 6-membered            non-aromatic heterocyclic group, the phenyl or heterocyclic            group being optionally substituted by one, two or three            groups independently selected from the group consisting of            halo, C₁₋₄alkyl and haloC₁₋₄alkyl; wherein when Y is CO, R²            is not (CH₂)₂pyrrolidinyl;        -   R^(2′) is selected from the group consisting of methyl and            ethyl;        -   R³ is selected from the group consisting of C₁₋₆alkyl and a            group —(CH₂)_(p)Z′ wherein p is 1, 2 or 3;        -   Z′ is hydroxy, methoxy, NHMe, phenyl or a 5- or 6-membered            non-aromatic or aromatic heterocyclic group, the phenyl or            heterocyclic group being optionally substituted by one, two            or three groups independently selected from the group            consisting of halo, C₁₋₄alkyl and haloC₁₋₄alkyl; or        -   R^(2′) and R³, together with the nitrogen atom to which they            are attached, form:            -   (i) a 4 or 5-membered non-aromatic heterocyclic group,                which ring is optionally substituted by one, two or                three groups independently selected from the group                consisting of halo, hydroxy, NR¹³R¹⁴ (wherein R¹³ and                R¹⁴ are independently selected from the group consisting                of hydrogen and C₁₋₄alkyl), haloC₁₋₄alkyl, and keto; or            -   (ii) a 6-membered non-aromatic heterocyclic group, which                ring is optionally substituted by one, two or three                groups independently selected from the group consisting                of halo, hydroxy, NR¹³R¹⁴ (wherein R¹³ and R¹⁴ are                independently selected from the group consisting of                hydrogen and C₁₋₄alkyl), C₂₋₄alkyl, haloC₁₋₄alkyl and                keto;    -   b) when n and m are both simultaneously 0, R¹ is selected from        the group consisting of:        -   C₁₋₆alkoxy;        -   a monocyclic saturated or partially unsaturated 5- or            6-membered heterocyclic group, attached through a carbon            atom and optionally substituted by one, two or three groups            independently selected from the group consisting of            C₁₋₄alkyl, C(O)C₁₋₄alkyl, haloC₁₋₄alkyl, halo and keto;        -   N-linked pyrrolidinyl, optionally substituted with one, two            or three groups independently selected from the group            consisting of C₁₋₄alkyl, C(O)C₁₋₄alkyl, halo C₁₋₄alkyl, halo            and keto; and        -   oxazolyl or imidazolyl, both being optionally substituted by            C₁₋₄alkyl;    -   c) when n is 1 or 2, and m is 1, R¹ is selected from the group        consisting of C₁₋₄alkyl, benzyl, cyclopropyl, thienyl, and        NR⁹R¹⁰ wherein:        -   R⁹ is selected from the group consisting of hydrogen and            C₁₋₄alkyl, and R¹⁰ is selected from the group consisting of            C₁₋₆ straight chain alkyl, C₃₋₆cycloalkyl and —(CH₂)_(p)Z            wherein p is 1, 2 or 3;        -   Z is a phenyl or a 5- or 6-membered heterocyclic group, the            phenyl or heterocyclic group being optionally substituted by            one, two or three groups independently selected from the            group consisting of halo and C₁₋₄alkyl; or        -   R⁹ and R¹⁰, together with the nitrogen atom to which they            are attached, form a 5-membered aromatic or non-aromatic            heterocyclic group or a 6-membered non-aromatic heterocyclic            group, any of the rings being optionally substituted by one,            two or three groups independently selected from the group            consisting of C₁₋₄alkyl, halo, phenyl and (in the case of a            non-aromatic ring) keto; and    -   d) when n is 1 or 2, and m is 0, R¹ is selected from the group        consisting of cyano, hydroxy, NH₂, a C-linked 5-membered        aromatic heterocyclic group optionally substituted with one, two        or three groups independently selected from the group consisting        of C₁₋₆alkyl and C₃₋₆cycloalkyl, and NR¹¹R¹² in which:        -   R¹¹ is hydrogen and R¹² is selected from the group            consisting of SO₂C₁₋₄alkyl, SO₂C₃₋₆cycloalkyl,            C(O)C₁₋₄alkyl, and C(O)C₂₋₄alkenyl; or R¹¹ is selected from            the group consisting of C₁₋₄alkyl and C₂₋₄alkenyl, and R¹²            is selected from the group consisting of SO₂C₁₋₄alkyl,            SO₂C₃₋₆cycloalkyl, C(O)C₁₋₄alkyl, C(O)phenyl and            C(O)C₂₋₄alkenyl or        -   R¹¹ and R¹², together with the nitrogen atom to which they            are attached, form a group selected from the group            consisting of:            -   (i) a 5-membered aromatic heterocyclic group which is                optionally substituted by one or two groups                independently selected from the group consisting of                C₁₋₄alkyl, halo, haloC₁₋₄alkyl, hydroxy, C₃₋₆cycloalkyl                and C₁₋₄alkoxy; and            -   (ii) imidazolyl substituted by phenyl;            -   (iii) a 5-membered non-aromatic heterocyclic group which                is substituted by one, two or three groups independently                selected from the group consisting of keto, hydroxy and                C₁₋₄alkoxy; and            -   (iv) a 6-membered non-aromatic heterocyclic group, which                is optionally substituted by one, two or three groups                independently selected from the group consisting of                keto, hydroxy and C₁₋₄alkoxy;    -   with the proviso that the compound is not        4-methyl-N-[4-[4,5,6,7-tetrahydro-3-(trifluoromethyl)-1H-indazol-1-yl]phenyl]-1,2,3-thiadiazole-5-carboxamide        and salts thereof, or a compound in which simultaneously n=0,        m=1, q=0, Y=CO and R¹ is selected from the group consisting of:        NMe₂, pyrrolidinyl, NMeCH₂Ph, morpholinyl, piperidyl, NHEt,        NEt₂, NHMe, NHCH₂-tetrahydrofuran-2-yl, NH(CH₂)₂Ph, NH(CH₂)Ph,        NHtBu, NHCH₂-furan-2-yl and NH(CH₂)₃OMe.

Examples of compounds of formula (A) include:

-   N,N-dimethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 1)-   N-ethyl-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 4)-   N-butyl-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 5)-   N-methyl-N-(2-phenylethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 6)-   N,N-dimethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide    (Example 7)-   1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}ethanone    (Example 8)-   1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-1-propanone    (Example 9)-   1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 10)-   1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-2-propanone    (Example 11)-   N,N-dimethyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 12)-   1-{4-[2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 13)-   N-ethyl-N-methyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 14)-   N-methyl-N-(phenylmethyl)-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 15)-   N-butyl-N-methyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 16)-   N-methyl-N-(2-phenylethyl)-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 17)-   1-{[4-(1-pyrrolidinylcarbonyl)phenyl]methyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 18)-   1-{4-[1-methyl-2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 19)-   N,N-dimethyl-3-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}propanamide    (Example 20)-   1-{4-[3-oxo-3-(1-pyrrolidinyl)propyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 21)-   1-{4-[1-(1-pyrrolidinylcarbonyl)cyclopropyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 22)-   1-{4-[2-oxo-2-(1-piperidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 23)-   1-{4-[2-(3,3-difluoro-1-pyrrolidinyl)-2-oxoethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 24)-   N-methyl-N-propyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 25)-   N-cyclopentyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 26)-   N-methyl-N-(2-thienylmethyl)-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 27)-   {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetonitrile    (Example 28)-   {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanol    (Example 29)-   N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide    (Example 30)-   1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-pyrrolidinone    (Example 31)-   N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)propanamide    (Example 32)-   N-ethyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide    (Example 33)-   1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-piperidinone    (Example 34)-   1-methyl-5-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-2-pyrrolidinone    (Example 35)-   N-[3-(1H-imidazol-1-yl)propyl]-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 36)-   N-methyl-N-[2-(2-thienyl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 37)-   N-methyl-N-[2-(1H-1,2,4-triazol-1-yl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 38)-   N-methyl-N-(1,3-thiazol-2-ylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 39)-   N-methyl-N-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 40)-   N-methyl-N-(2-thienylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 41)-   N-methyl-N-(3-pyridinylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 42)-   N-(2-furanyl    methyl)-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 43)-   N-[(4-fluorophenyl)methyl]-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 44)-   N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)methanesulfonamide    (Example 46)-   1-{4-[1-fluoro-2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   1-{4-[,    1-difluoro-2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)methanesulfonamide-   1-(4-{[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]methyl}phenyl)-2-pyrrolidinone-   N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-1-pyrrolidinecarboxamide-   5-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-2-pyrrolidinone-   N-(1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}ethyl)acetamide-   N-methyl-N-(1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}ethyl)acetamide-   1-[4-(1-acetyl-2-pyrrolidinyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   1-(2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}ethyl)-2-pyrrolidinone-   1-{4-[(1,1-dioxido-2-isothiazolidinyl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   2-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)propanamide-   N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)butanamide-   N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-thiophenecarboxamide-   N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)propanamide-   N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide-   N-methyl-2-phenyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide-   N-(2-hydroxyethyl)-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   N-methyl-N-[2-(methyloxy)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   N-methyl-N-[2-(methylamino)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}carbonyl)-3-pyrrolidinol-   N-methyl-1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}carbonyl)-3-pyrrolidinamine-   1-[4-(1-azetidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}carbonyl)-3-azetidinol-   (3,3-difluorocyclobutyl){4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanone-   1-[4-(1H-imidazol-1-yl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propenamide-   N-(1-methylethenyl)-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propenamide-   N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propenamide-   1-{4-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   1-{4-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   N-methyl-N-(1-methylethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   1-{4-[2-oxo-2-(2-phenyl-1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)benzamide-   1-[4-(1,3-oxazol-5-yl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   1-[4-(propyloxy)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   1-[4-(1-methyl-1H-imidazol-4-yl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propanesulfonamide-   N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)cyclopropanesulfonamide-   N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)cyclopentanesulfonamide-   1-[4-(1-pyrrolidinylsulfonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   N-(2-methylpropyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide-   1-[4-(4-morpholinylsulfonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   N-[2-(methyloxy)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide-   N-[2-(1-pyrrolidinyl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide-   N-(tetrahydro-2-furanylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide-   1-[4-(1H-imidazol-1-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   1-[4-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   1-[4-(1H-pyrazol-1-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   1-[4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   1-[4-(2H-1,2,3-triazol-2-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   1-{4-[(4-methyl-1H-pyrazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   1-{4-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   3-(trifluoromethyl)-1-(4-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)-4,5,6,7-tetrahydro-1H-indazole-   3-(trifluoromethyl)-1-(4-{[5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)-4,5,6,7-tetrahydro-1H-indazole-   1-(4-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   1-(4-{[3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   1-{4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   1-(4-{[2-(1-methylethyl)-1H-imidazol-1-yl]methyl}phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   1-{4-[(4-phenyl-1H-imidazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   1-{4-[(4-bromo-1H-pyrazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   N-methyl-1H-imidazol-2-yl){4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanone    and-   N-methyl-N-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-1-pyrrolidinecarboxamide.

In one embodiment, a compound of formula (I) is a compound in which n=0and m=1, that is to say a compound of formula (Ia), in which q, Y and R¹are as set out for formula (I) above, excluding4-methyl-N-[4-[4,5,6,7-tetrahydro-3-(trifluoromethyl)-1H-indazol-1-yl]phenyl]-1,2,3-thiadiazole-5-carboxamideand salts and solvates thereof:

In one embodiment, in formula (Ia), q is 0.

In one embodiment, in formula (Ia), Y is selected from the groupconsisting of CO, SO₂ and NMeCO. In one embodiment, Y is CO or SO₂. In afurther embodiment, Y is CO.

In one embodiment, in formula (Ia), R¹ is C₁₋₄alkyl.

In one embodiment, in formula (Ia), R¹ is a C-linked 5-membered aromaticheterocyclic group optionally substituted by methyl. In one embodiment,in formula (Ia), R¹ is selected from the group consisting of pyrrolyl,pyrrolinyl, pyrazolinyl, oxazolyl, isoxazoyl, imidazolyl, pyrazolyl,oxadiazolyl, isothiazolyl, thiazolyl, triazolyl, furyl and thienyl, eachgroup being optionally substituted by methyl. In one embodiment, informula (Ia), R¹ is imidazolyl optionally substituted with methyl.

In one embodiment, in formula (Ia), R¹ is a group NHR² wherein R² isselected from the group consisting of C₁₋₆straight chain alkyl andC₄₋₆branched chain alkyl.

In one embodiment, in formula (Ia), R¹ is a group NHR² wherein R² isselected from the group consisting of methyl and ethyl.

In one embodiment, in formula (Ia), R¹ is a group NHR² wherein R² is agroup —(CH₂)_(p)Z wherein p is 1, 2 or 3, and Z is selected from thegroup consisting of hydroxy, methoxy and NHMe.

In one embodiment, in formula (Ia), R¹ is a group NHR² wherein R² is agroup —(CH₂)_(p)Z wherein p is 1, 2 or 3, and Z is selected from thegroup consisting of phenyl, imidazolyl, thienyl, triazolyl, thiazolyl,pyrrolyl, pyridyl, furanyl, pyrrolidynl and tetrahydrofuranyl, eachgroup being optionally substituted by one or two groups independentlyselected from the group consisting of halo, C₁₋₄alkyl and haloC₁₋₄alkyl;wherein when Y is CO, R² is not (CH₂)₂pyrrolidinyl.

In one embodiment, in formula (Ia), R¹ is NR^(2′)R³, wherein R² isselected from the group consisting of methyl and ethyl; and R³ isC₁₋₆alkyl.

In one embodiment, in formula (Ia), R¹ is NR^(2′)R³, wherein R² isselected from the group consisting of methyl and ethyl; and R³ isselected from the group consisting of methyl, ethyl, propyl, isopropyl,butyl and t-butyl.

In one embodiment, in formula (Ia), R¹ is NR^(2′)R³, wherein R² isselected from the group consisting of methyl and ethyl and R³ is a group—(CH₂)_(p)Z′ wherein p is 1, 2 or 3 and Z′ is hydroxy, methoxy or NHMe.

In one embodiment, in formula (Ia), R¹ is NR^(2′)R³, wherein R² isselected from the group consisting of methyl and ethyl and R³ is a group—(CH₂)_(p)Z′ wherein p is 1, 2 or 3 and Z′ is selected from the groupconsisting of phenyl, imidazolyl, thienyl, triazolyl, thiazolyl,pyrrolyl, pyridyl, furanyl, pyrrolidinyl and tetrahydrofuranyl, eachgroup being optionally substituted by one or two groups independentlyselected from the group consisting of halo, C₁₋₄alkyl and haloC₁₋₄alkyl.

In one embodiment, in formula (Ia), R¹ is NR^(2′)R³, and R^(2′) and R³,together with the nitrogen atom to which they are attached, form:

-   -   a 4 or 5-membered non-aromatic heterocyclic group, which ring is        optionally substituted by one, two or three groups independently        selected from the group consisting of halo, hydroxy, NR¹³R¹⁴        (wherein R¹³ and R¹⁴ are independently selected from the group        consisting of hydrogen and C₁₋₄alkyl), haloC₁₋₄alkyl, and keto.

In one embodiment, in formula (Ia), R¹ is NR^(2′)R³, and R^(2′) and R³,together with the nitrogen atom to which they are attached, form:

-   -   pyrrolidinyl or azetidinyl, both of which is optionally        substituted by one, two or three groups independently selected        from the group consisting of halo, hydroxy, NR¹³R¹⁴ (wherein R¹³        and R¹⁴ are independently selected from the group consisting of        hydrogen and C₁₋₄alkyl), haloC₁₋₄alkyl, and keto.

In one embodiment, in formula (Ia), R¹ is NR^(2′)R³, and R^(2′) and R³,together with the nitrogen atom to which they are attached, form:

-   -   pyrrolidinyl or azetidinyl, both of which is optionally        substituted by one or two groups independently selected from the        group consisting of hydroxy, NMe and fluoro.

In one embodiment, in formula (Ia), R¹ is NR^(2′)R³, and R^(2′) and R³,together with the nitrogen atom to which they are attached, form:

-   -   a 6-membered non-aromatic heterocyclic group, which ring is        optionally substituted by one, two or three groups independently        selected from the group consisting of halo, hydroxy, NR¹³R¹⁴        (wherein R¹³ and R¹⁴ are independently selected from the group        consisting of hydrogen and C₁₋₄alkyl), C₂₋₄alkyl, haloC₁₋₄alkyl        and keto.

In one embodiment, in formula (Ia), R¹ is NR^(2′)R³, and R^(2′) and R³,together with the nitrogen atom to which they are attached, form:

-   -   piperidyl, morpholinyl or piperazinyl, any of which is        optionally substituted by one, two or three groups independently        selected from the group consisting of halo, hydroxy, NR¹³R¹⁴        (wherein R¹³ and R¹⁴ are independently selected from the group        consisting of hydrogen and C₁₋₄alkyl), C₂₋₄alkyl, haloC₁₋₄alkyl        and keto.

In one embodiment, in formula (Ia), R¹ is NR^(2′)R³, and R^(2′) and R³,together with the nitrogen atom to which they are attached, form:

-   -   piperidyl, morpholinyl or piperazinyl, any of which is        optionally substituted by one, two or three groups independently        selected from the group consisting of halo, hydroxy, NR¹³R¹⁴        (wherein R¹³ and R¹⁴ are independently selected from the group        consisting of hydrogen and C₁₋₄alkyl), C₂₋₄alkyl, haloC₁₋₄alkyl        and keto.

In a further embodiment, R² and R³ together with the nitrogen atom towhich they are attached form a pyrrolidinyl ring, which may besubstituted with one or more groups selected from halo, C₁₋₄alkyl,haloC₁₋₄alkyl, or keto. In an embodiment, R² and R³ together with thenitrogen atom to which they are attached form a pyrrolidinonyl ring or apyrrolidinyl ring.

In one embodiment, in formula (Ia), Y is CO, and R¹ is selected from thegroup consisting of (i) C₁₋₄alkyl and (ii) a C-linked 5-memberedaromatic heterocyclic group optionally substituted with methyl.

In one embodiment, in formula (Ia), Y is CO, and R¹ is selected from thegroup consisting of methyl, ethyl, and imidazolyl optionally substitutedwith one methyl.

In one embodiment, in formula (Ia), Y is CO, and R¹ is selected from thegroup consisting of NHR² and NR^(2′)R³, wherein:

-   -   R² is selected from the group consisting of C₁₋₆straight chain        alkyl, C₄₋₆branched chain alkyl and a group —(CH₂)_(p)Z wherein        p is 1, 2 or 3;    -   Z is hydroxy, methoxy, NHMe, phenyl or a 5- or 6-membered        non-aromatic heterocyclic group, the phenyl or heterocyclic        group being optionally substituted by one, two or three groups        independently selected from the group consisting of halo,        C₁₋₄alkyl and haloC₁₋₄alkyl;    -   R^(2′) is selected from the group consisting of methyl and        ethyl;    -   R³ is selected from the group consisting of C₁₋₆alkyl and a        group —(CH₂)_(p)Z′ wherein p is 1, 2 or 3;    -   Z′ is hydroxy, methoxy, NHMe, phenyl or a 5- or 6-membered        non-aromatic or aromatic heterocyclic group, the phenyl or        heterocyclic group being optionally substituted by one, two or        three groups independently selected from the group consisting of        halo, C₁₋₄alkyl and haloC₁₋₄alkyl.

In one embodiment, in formula (Ia), Y is CO, and R¹ is a group NHR²wherein:

-   -   R² is selected from the group consisting of C₁₋₆straight chain        alkyl and C₄₋₆branched chain alkyl.

In one embodiment, in formula (Ia), Y is CO, and R¹ is a group NHR²wherein:

-   -   R² is selected from the group consisting of methyl and ethyl.

In one embodiment, in formula (Ia), Y is CO, and R¹ is a group NHR²wherein:

-   -   R² is a group —(CH₂)_(p)Z wherein p is 1, 2 or 3 and Z is        hydroxy, methoxy, or NHMe.

In one embodiment, in formula (Ia), Y is CO, and R¹ is a group NHR²wherein:

-   -   R² is a group —(CH₂)_(p)Z wherein p is 1, 2 or 3 and Z is        selected from the group consisting of phenyl, imidazolyl,        thienyl, triazolyl, thiazolyl, pyrrolyl, pyridyl, furanyl and        tetrahydrofuranyl, each group being optionally substituted by        one or two groups independently selected from the group        consisting of halo, C₁₋₄alkyl and haloC₁₋₄alkyl.

In one embodiment, in formula (Ia), Y is CO, and R¹ is NR^(2′)R³,wherein:

-   -   R^(2′) is selected from the group consisting of methyl and        ethyl; and    -   R³ is C₁₋₆alkyl.

In one embodiment, in formula (Ia), Y is CO, and R¹ is NR^(2′)R³,wherein:

-   -   R^(2′) is selected from the group consisting of methyl and        ethyl;    -   R³ is a group —(CH₂)_(p)Z′ wherein p is 1, 2 or 3 and Z′ is        hydroxy, methoxy or NHMe.

In one embodiment, in formula (Ia), Y is CO, and R¹ is NR^(2′)R³,wherein:

-   -   R^(2′) is selected from the group consisting of methyl and        ethyl;    -   R³ is a group —(CH₂)_(p)Z′ wherein p is 1, 2 or 3 and Z′ is        selected from the group consisting of phenyl, imidazolyl,        thienyl, triazolyl, thiazolyl, pyrrolyl, pyridyl, furanyl,        pyrrolidynl and tetrahydrofuranyl, each group being optionally        substituted by one or two groups independently selected from the        group consisting of halo, C₁₋₄alkyl and haloC₁₋₄alkyl.

In one embodiment, in formula (Ia), Y is CO, R¹ is NR^(2′)R³, and R^(2′)and R³, together with the nitrogen atom to which they are attached,form:

-   -   a 4 or 5-membered non-aromatic heterocyclic group, which ring is        optionally substituted by one, two or three groups independently        selected from the group consisting of halo, hydroxy, NR¹³R¹⁴        (wherein R¹³ and R¹⁴ are independently selected from the group        consisting of hydrogen and C₁₋₄alkyl), haloC₁₋₄alkyl, and keto.

In one embodiment, in formula (Ia), Y is CO, R¹ is NR^(2′)R³, and R^(2′)and R³, together with the nitrogen atom to which they are attached,form:

-   -   pyrrolidinyl or azetidinyl, both of which is optionally        substituted by one, two or three groups independently selected        from the group consisting of halo, hydroxy, NR¹³R¹⁴ (wherein R¹³        and R¹⁴ are independently selected from the group consisting of        hydrogen and C₁₋₄alkylhaloC₁₋₄alkyl, and keto.

In one embodiment, in formula (Ia), Y is CO, R¹ is NR^(2′)R³, and R^(2′)and R³, together with the nitrogen atom to which they are attached,form:

-   -   pyrrolidinyl or azetidinyl, both of which is optionally        substituted by one or two groups independently selected from the        group consisting of hydroxy, NMe and fluoro.

In one embodiment, in formula (Ia), Y is CO, R¹ is NR^(2′)R³, and R^(2′)and R³, together with the nitrogen atom to which they are attached,form:

-   -   a 6-membered non-aromatic heterocyclic group, which ring is        optionally substituted by one, two or three groups independently        selected from the group consisting of halo, hydroxy, NR¹³R¹⁴        (wherein R¹³ and R¹⁴ are independently selected from the group        consisting of hydrogen and C₁₋₄alkyl), C₂₋₄alkyl, haloC₁₋₄alkyl        and keto.

In one embodiment, in formula (Ia), Y is CO, R¹ is NR^(2′)R³, and R^(2′)and R³, together with the nitrogen atom to which they are attached,form:

-   -   piperidyl, morpholinyl or piperazinyl, any of which is        optionally substituted by one, two or three groups independently        selected from the group consisting of halo, hydroxy, NR¹³R¹⁴        (wherein R¹³ and R¹⁴ are independently selected from the group        consisting of hydrogen and C₁₋₄alkyl), C₂₋₄alkyl, haloC₁₋₄alkyl        and keto.

In one embodiment, in formula (Ia), Y is CO, R¹ is NR^(2′)R³, and R^(2′)and R³, together with the nitrogen atom to which they are attached,form:

-   -   piperidyl, morpholinyl or piperazinyl, any of which is        optionally substituted by one, two or three groups independently        selected from the group consisting of halo, hydroxy, NR¹³R¹⁴        (wherein R¹³ and R¹⁴ are independently selected from the group        consisting of hydrogen and C₁₋₄alkyl), C₂₋₄alkyl, haloC₁₋₄alkyl        and keto.

In one embodiment, in formula (Ia), Y is NR⁸CO, SO, SO₂ or NR⁸SO₂, andR¹ is C₁₋₄alkyl.

In one embodiment, formula (Ia), Y is NR⁸CO, SO, SO₂ or NR⁸SO₂, and R¹is methyl.

In one embodiment, formula (Ia), Y is NR⁸CO, SO, SO₂ or NR⁸SO₂, and R¹is a group NHR², wherein R² is selected from the group consisting ofC₁₋₆straight chain alkyl and C₄₋₆branched chain alkyl.

In one embodiment, formula (Ia), Y is NR⁸CO, SO, SO₂ or NR⁸SO₂, and R¹is a group NHR², wherein R² is t-butyl.

In one embodiment, formula (Ia), Y is NR⁸CO, SO, SO₂ or NR⁸SO₂, and R¹is a group NHR², wherein R² is a group —(CH₂)_(p)Z wherein p is 1, 2 or3 and Z is hydroxy, methoxy or NHMe.

In one embodiment, formula (Ia), Y is NR⁸CO, SO, SO₂ or NR⁸SO₂, and R¹is a group NHR², wherein R² is a group —(CH₂)_(p)Z wherein p is 1, 2 or3 and Z is phenyl or a 5- or 6-membered non-aromatic heterocyclic group,the phenyl or heterocyclic group being optionally substituted by one,two or three groups independently selected from the group consisting ofhalo, C₁₋₄alkyl and haloC₁₋₄alkyl.

In one embodiment, formula (Ia), Y is NR⁸CO, SO, SO₂ or NR⁸SO₂, and R¹is a group NHR², wherein R² is a group —(CH₂)_(p)Z wherein p is 1, 2 or3 and Z is pyrrolidinyl or tetrahydrofuranyl.

In one embodiment, in formula (Ia), Y is NR⁸CO, SO, SO₂ or NR⁸SO₂, andR¹ is NR^(2′)R³, wherein R^(2′) is selected from the group consisting ofmethyl and ethyl; and R³ is C₁₋₆alkyl.

In one embodiment, in formula (Ia), Y is NR⁸CO, SO, SO₂ or NR⁸SO₂, andR¹ is NR^(2′)R³, wherein R^(2′) is selected from the group consisting ofmethyl and ethyl; and R³ is selected from the group consisting of methyland ethyl.

In one embodiment, in formula (Ia), Y is NR⁸CO, SO, SO₂ or NR⁸SO₂, andR¹ is NR^(2′)R³, wherein:

-   -   R^(2′) is selected from the group consisting of methyl and        ethyl;    -   R³ is a group —(CH₂)_(p)Z′ wherein p is 1, 2 or 3;    -   Z′ is hydroxy, methoxy or NHMe.

In one embodiment, in formula (Ia), Y is NR⁸CO, SO, SO₂ or NR⁸SO₂, andR¹ is NR^(2′)R³, wherein:

-   -   R^(2′) is selected from the group consisting of methyl and        ethyl;    -   Z′ is phenyl or a 5- or 6-membered non-aromatic or aromatic        heterocyclic group, the phenyl or heterocyclic group being        optionally substituted by one, two or three groups independently        selected from the group consisting of halo, C₁₋₄alkyl and        haloC₁₋₄alkyl. In one embodiment, in formula (Ia), R¹ is        NR^(2′)R³, wherein:    -   R^(2′) and R³, together with the nitrogen atom to which they are        attached, form azetidinyl, pyrrolidinyl, morpholinyl or        piperidyl, each group being optionally substituted by one or two        groups independently selected from the group consisting of halo,        hydroxy, NHMe, C₁₋₄alkyl, haloC₁₋₄alkyl and keto.

In one embodiment, a compound of formula (I) is a compound in which n=0and m=0, that is to say a compound of formula (Ib), in which q, and R¹are as set out for formula (I) above:

In one embodiment, in formula (Ib), q is 0.

In one embodiment, in formula (Ib), R¹ is C₁₋₆alkoxy. In one embodiment,R¹ is methoxy, ethoxy or propoxy.

In one embodiment, in formula (Ib), R¹ is N- or C-linked pyrrolidinyl,optionally substituted by one or two groups selected from the groupconsisting of C₁₋₄alkyl, C(O)C₁₋₄alkyl and keto. In one embodiment, R¹is a 2-pyrrolidinonyl attached through a nitrogen or a carbon atom, or aN-methyl 2-pyrrolidinonyl group attached through a carbon atom.

In one embodiment, in formula (Ib), R¹ is oxazolyl or imidazolyl, bothbeing optionally substituted by a methyl.

In one embodiment, a compound of formula (I) is a compound in which n=1or 2 and m=1, that is to say a compound of formula (Ic), in which q, Yand R¹ are as set out for formula (I) above:

In one embodiment, in formula (Ic), q is 0.

In one embodiment, in formula (Ic), Y is selected from the groupconsisting of CO, NR⁸SO₂ and NR⁸CO, wherein R⁸ is hydrogen or C₁₋₂alkyl.In one embodiment, Y is selected from the group consisting of CO, NHCO,NMeCO, NEtCO, NHSO₂ and NMeSO₂.

In one embodiment, in formula (Ic), X is selected from the groupconsisting of CH₂, CHMe, CF₂ and CR⁶R⁷, wherein R⁶ and R⁷, together withthe carbon atom to which they are attached, form a 3-memberedcarbocyclic ring. In one embodiment, X is CH₂.

In one embodiment, in formula (Ic), R¹ is selected from the groupconsisting of C₁₋₄alkyl, benzyl, cyclopropyl and thienyl.

In one embodiment, in formula (Ic), R¹ is NR⁹R¹⁰ wherein:

-   -   R⁹ is selected from the group consisting of hydrogen and        C₁₋₄alkyl, and R¹⁰ is selected from the group consisting of C₁₋₆        straight chain alkyl, C₃₋₆cycloalkyl and —(CH₂)_(p)Z wherein p        is 1, 2 or 3 and Z is a phenyl or a 5- or 6-membered        heterocyclic group, the phenyl or heterocyclic group being        optionally substituted by one, two or three groups independently        selected from the group consisting of halo and C₁₋₄alkyl.

In one embodiment, in formula (Ic), R¹ is NR⁹R¹⁰ wherein:

-   -   R⁹ is selected from the group consisting of hydrogen and methyl,        and R¹⁰ is selected from the group consisting of C₁₋₆ straight        chain alkyl, C₃₋₆cycloalkyl and —(CH₂)_(p)Z wherein p is 1, 2 or        3; and Z is phenyl or thienyl.

In one embodiment, in formula (Ic), R¹ is NR⁹R¹⁰ wherein:

-   -   R⁹ and R¹⁰, together with the nitrogen atom to which they are        attached, form a 5- or 6-membered non-aromatic heterocyclic        group being optionally substituted by one, two or three groups        independently selected from the group consisting of C₁₋₄alkyl,        halo, phenyl and keto.

In one embodiment, in formula (Ic), R¹ is NR⁹R¹⁰ wherein:

-   -   R⁹ and R¹⁰, together with the nitrogen atom to which they are        attached, form a pyrrolidinyl or piperidyl ring, both ring being        optionally substituted by one or two groups independently        selected from the group consisting of C₁₋₄alkyl, halo, phenyl        and keto.

In one embodiment, in formula (Ic), R¹ is NR⁹R¹⁰ wherein:

-   -   R⁹ and R¹⁰, together with the nitrogen atom to which they are        attached, form a pyrrolidinyl or piperidyl ring, both ring being        optionally substituted by one or two fluoro.

In one embodiment, a compound of formula (I) is a compound in which n=1or 2 and m=0, that is to say a compound of formula (Id), in which q, n,X and R′ are as set out for formula (I) above:

In one embodiment, in formula (Id), q is 0.

In one embodiment, in formula (Id), a compound of formula (Id) is acompound in which X is selected from the group consisting of CH₂, CHMeand (when n=1) CR⁶R⁷, where R⁶ and R⁷, together with the carbon atom towhich they are attached, form a 3-membered carbocyclic ring. In oneembodiment, X is CH₂.

In one embodiment, in formula (Id), n is 1.

In one embodiment, in formula (Id), R¹ is selected from the groupconsisting of cyano and hydroxy.

In one embodiment, in formula (Id), R¹ is a C-linked 5-membered aromaticheterocyclic group optionally substituted by one, two or three groupsindependently selected from the group consisting of C₁₋₆alkyl andC₃₋₆cycloalkyl. In one embodiment, R¹ is oxadiazolyl optionallysubstituted by one or two groups independently selected from the groupconsisting of C₁₋₆alkyl and C₃₋₆cycloalkyl. In one embodiment, R¹ isoxadiazolyl substituted by a methyl or cyclopropyl.

In one embodiment, in formula (Id), R¹ is a group NHR¹² in which:

-   -   R¹² is selected from the group consisting of SO₂C₃₋₆cycloalkyl        and C(O)C₂₋₄alkenyl.

In one embodiment, in formula (Id), R¹ is a group NHR¹² in which:

-   -   R¹² is selected from CO(CH═CH₂) and SO₂-cyclopentanyl.

In one embodiment, in formula (Id), R¹ is a group NR¹¹R¹² in which:

-   -   R¹¹ is selected from the group consisting of C₁₋₄alkyl and        C₂₋₄alkenyl, and R¹² is selected from the group consisting of        C(O)C₁₋₄alkyl, C(O)phenyl and C(O)C₂₋₄alkenyl.

In one embodiment, in formula (Id), R¹ is a group NR¹¹R¹² in which:

-   -   R¹¹ is selected from the group consisting of C₁₋₄alkyl and        C₂₋₄alkenyl, and R¹² is selected from the group consisting of        COMe, C(O)phenyl and C(O)(CH═CH₂).

In one embodiment, in formula (Id), R¹ is a group NR¹¹R¹² in which:

-   -   R¹¹ and R¹², together with the nitrogen atom to which they are        attached, form a group selected from the group consisting of:        -   pyrazolyl, imidazolyl and triazolyl, each being optionally            substituted by one or two groups independently selected from            the group consisting of C₁₋₄alkyl, halo and haloC₁₋₄alkyl;            and        -   imidazolyl substituted by phenyl; and        -   pyrrolidinyl or isothiazolidinyl, each substituted by one or            two keto, hydroxy and C₁₋₄alkoxy; and        -   piperidyl, optionally substituted by one or two groups            independently selected from the group consisting of keto,            hydroxy and C₁₋₄alkoxy.

In one embodiment, in formula (Id), R¹ is a group NR¹¹R¹² in which:

-   -   R¹¹ and R¹², together with the nitrogen atom to which they are        attached, form a group selected from the group consisting of:        -   (i) pyrazolyl, imidazolyl and triazolyl, each being            optionally substituted by one or two groups independently            selected from the group consisting of methyl, isopropyl,            halo and CF₃; and        -   (ii) imidazolyl substituted by phenyl; and        -   (iii) pyrrolidinyl or isothiazolidinyl, each substituted by            one or two keto; and        -   (iv) piperidyl, optionally substituted by a keto.

In one embodiment, the present invention provides a compound of formula(Ie) or a salt or solvate thereof:

wherein:

-   -   q is 0 or 1;    -   n is 0, 1, or 2;    -   X is CR⁶R⁷, where R⁶ and R⁷ are each independently selected from        the group consisting of hydrogen, methyl and fluoro, but R⁶ and        R⁷ are not both simultaneously methyl; or, when n is 1, R⁶ and        R⁷ together with the carbon atom to which they are attached,        form a 3-membered carbocyclic ring;    -   Y is selected from the group consisting of CO, NR⁸CO, SO, SO₂        and NR⁸SO₂;    -   R⁸ is selected from the group consisting of hydrogen,        C₂₋₄alkenyl and C₁₋₄alkyl;    -   m is 0 or 1; and    -   a) when n is 0 and m=1, then R¹ is selected from the group        consisting of (i) C₁₋₄alkyl, (ii) imidazolyl optionally        substituted with methyl, and, (iii) NHR² and (iv) NR²R³,        wherein:        -   R² is selected from the group consisting of C₁₋₆straight            chain alkyl, C₄₋₆branched chain alkyl and a group            —(CH₂)_(p)Z wherein p is 1, 2 or 3;        -   Z is hydroxy, methoxy, NHMe, phenyl or a 5- or 6-membered            non-aromatic heterocyclic group, the phenyl or heterocyclic            group being optionally substituted by one, two or three            groups independently selected from the group consisting of            halo, C₁₋₄alkyl and haloC₁₋₄alkyl; wherein when Y is CO, R²            is not (CH₂)₂pyrrolidinyl;        -   R^(2′) is selected from the group consisting of methyl and            ethyl;        -   R³ is selected from the group consisting of C₁₋₆alkyl and a            group —(CH₂)_(p)Z′ wherein p is 1, 2 or 3;        -   Z′ is hydroxy, methoxy, NHMe, phenyl or a 5- or 6-membered            non-aromatic or aromatic heterocyclic group, the phenyl or            heterocyclic group being optionally substituted by one, two            or three groups independently selected from the group            consisting of halo, C₁₋₄alkyl and haloC₁₋₄alkyl;        -   R^(2′) and R³, together with the nitrogen atom to which they            are attached, form:            -   (i) a 4 or 5-membered non-aromatic heterocyclic group,                which ring is optionally substituted by one, two or                three groups independently selected from the group                consisting of halo, hydroxy, NR¹³R¹⁴ (wherein R¹³ and                R¹⁴ are independently selected from the group consisting                of hydrogen and C₁₋₄alkyl), haloC₁₋₄alkyl, and keto; or            -   (ii) a 6-membered non-aromatic heterocyclic group, which                ring is optionally substituted by one, two or three                groups independently selected from the group consisting                of halo, hydroxy, NR¹³R¹⁴ (wherein R¹³ and R¹⁴ are                independently selected from the group consisting of                hydrogen and C₁₋₄alkyl), C₂₋₄alkyl, haloC₁₋₄alkyl and                keto;    -   b) when n and m are both simultaneously 0, R¹ is selected from        the group consisting of:        -   C₁₋₆alkoxy;        -   a monocyclic saturated or partially unsaturated 5- or            6-membered heterocyclic group, attached through a carbon            atom and optionally substituted by one, two or three groups            independently selected from the group consisting of            C₁₋₄alkyl, C(O)C₁₋₄alkyl, haloC₁₋₄alkyl, halo and keto;        -   N-linked pyrrolidinyl, optionally substituted with one, two            or three groups independently selected from the group            consisting of C₁₋₄alkyl, C(O)C₁₋₄alkyl, halo C₁₋₄alkyl, halo            and keto; and        -   oxazolyl or imidazolyl, both being optionally substituted by            C₁₋₄alkyl;    -   c) when n is 1 or 2, and m is 1, R¹ is selected from the group        consisting of C₁₋₄alkyl, benzyl, cyclopropyl, thienyl, and        NR⁹R¹⁰ wherein:        -   R⁹ is selected from the group consisting of hydrogen and            C₁₋₄alkyl, and R¹⁰ is selected from the group consisting of            C₁₋₆ straight chain alkyl, C₃₋₆cycloalkyl and —(CH₂)_(p)Z            wherein p is 1, 2 or 3;        -   Z is a phenyl or a 5- or 6-membered heterocyclic group, the            phenyl or heterocyclic group being optionally substituted by            one, two or three groups independently selected from the            group consisting of halo and C₁₋₄alkyl; or        -   R⁹ and R¹⁰, together with the nitrogen atom to which they            are attached, form a 5-membered aromatic or non-aromatic            heterocyclic group or a 6-membered non-aromatic heterocyclic            group, any of the rings being optionally substituted by one,            two or three groups independently selected from the group            consisting of C₁₋₄alkyl, halo, phenyl and (in the case of a            non-aromatic ring) keto; and    -   d) when n is 1 or 2, and m is 0, R¹ is selected from the group        consisting of cyano, hydroxy, NH₂, a C-linked 5-membered        aromatic heterocyclic group optionally substituted with one, two        or three groups independently selected from the group consisting        of C₁₋₆alkyl and C₃₋₆cycloalkyl, and NR¹¹R¹² in which:        -   R¹¹ is hydrogen and R¹² is selected from the group            consisting of SO₂C₁₋₄alkyl, SO₂C₃₋₆cycloalkyl,            C(O)C₁₋₄alkyl, and C(O)C₂₋₄alkenyl; or R¹¹ is selected from            the group consisting of C₁₋₄alkyl and C₂₋₄alkenyl, and R¹²            is selected from the group consisting of SO₂C₁₋₄alkyl,            SO₂C₃₋₆cycloalkyl, C(O)C₁₋₄alkyl, C(O)phenyl and            C(O)C₂₋₄alkenyl or        -   R¹¹ and R¹², together with the nitrogen atom to which they            are attached, form a group selected from the group            consisting of:            -   (i) a 5-membered aromatic heterocyclic group which is                optionally substituted by one or two groups                independently selected from the group consisting of                C₁₋₄alkyl, halo, haloC₁₋₄alkyl, hydroxy, C₃₋₆cycloalkyl                and C₁₋₄alkoxy; and            -   (ii) imidazolyl substituted by phenyl;            -   (iii) a 5-membered non-aromatic heterocyclic group which                is substituted by one, two or three groups independently                selected from the group consisting of keto, hydroxy and                C₁₋₄alkoxy; and            -   (iv) a 6-membered non-aromatic heterocyclic group, which                is optionally substituted by one, two or three groups                independently selected from the group consisting of                keto, hydroxy and C₁₋₄alkoxy.

In one embodiment, in formula (Ie) above, the compound is not a compoundin which simultaneously n=0, m=1, q=0, Y=CO and R¹ is selected from thegroup consisting of: NMe₂, pyrrolidinyl, NMeCH₂Ph, morpholinyl,piperidyl, NHEt, NEt₂, NHMe, NHCH₂-tetrahydrofuran-2-yl, NH(CH₂)₂Ph,NH(CH₂)Ph, NHtBu, NHCH₂-furan-2-yl and NH(CH₂)₃OMe.

In one embodiment, the present invention provides a compound of formula(If) or a salt or solvate thereof:

wherein:

-   -   q is 0 or 1;    -   n is 0, 1, or 2;    -   X is CR⁶R⁷, where R⁶ and R⁷ are each independently selected from        the group consisting of hydrogen, methyl and fluoro, but R⁶ and        R⁷ are not both simultaneously methyl; or, when n is 1, R⁶ and        R⁷ together with the carbon atom to which they are attached,        form a 3-membered carbocyclic ring;    -   Y is selected from the group consisting of CO, NR⁸CO, SO, SO₂        and NR⁸SO₂;    -   R⁸ is selected from the group consisting of hydrogen,        C₂₋₄alkenyl and C₁₋₄alkyl;    -   m is 0 or 1; and    -   (a)(i) when n is 0 and m=1 and Y is CO, then R¹ is selected from        the group consisting of (i) C₁₋₄alkyl, (ii) a C-linked        5-membered aromatic heterocyclic group optionally substituted        with methyl, (iii) NHR² and (iv) NR^(2′)R³, wherein:        -   R² is selected from the group consisting of C₁₋₆straight            chain alkyl, C₄₋₆branched chain alkyl and a group            —(CH₂)_(p)Z wherein p is 1, 2 or 3;        -   Z is hydroxy, methoxy, NHMe, phenyl or a 5- or 6-membered            non-aromatic heterocyclic group, the phenyl or heterocyclic            group being optionally substituted by one, two or three            groups independently selected from the group consisting of            halo, C₁₋₄alkyl and haloC₁₋₄alkyl;        -   R^(2′) is selected from the group consisting of methyl and            ethyl;        -   R³ is selected from the group consisting of C₁₋₆alkyl and a            group —(CH₂)_(p)Z′ wherein p is 1, 2 or 3;        -   Z′ is hydroxy, methoxy, NHMe, phenyl or a 5- or 6-membered            non-aromatic or aromatic heterocyclic group, the phenyl or            heterocyclic group being optionally substituted by one, two            or three groups independently selected from the group            consisting of halo, C₁₋₄alkyl and haloC₁₋₄alkyl; or        -   R^(2′) and R³, together with the nitrogen atom to which they            are attached, form:            -   (i) a 4 or 5-membered non-aromatic heterocyclic group,                which ring is optionally substituted by one, two or                three groups independently selected from the group                consisting of halo, hydroxy, NR¹³R¹⁴ (wherein R¹³ and                R¹⁴ are independently selected from the group consisting                of hydrogen and C₁₋₄alkyl), haloC₁₋₄alkyl, and keto; or            -   (ii) a 6-membered non-aromatic heterocyclic group, which                ring is optionally substituted by one, two or three                groups independently selected from the group consisting                of halo, hydroxy, NR¹³R¹⁴ (wherein R¹³ and R¹⁴ are                independently selected from the group consisting of                hydrogen and C₁₋₄alkyl), C₂₋₄alkyl, haloC₁₋₄alkyl and                keto;    -   (a)(ii) when n is 0 and m=1 and Y is NR⁸CO, SO, SO₂ or NR⁸SO₂,        then R¹ is selected from the group consisting of (i)        C₁₋₄alkyl, (ii) NHR² and (iii) NR²R³, wherein:        -   R² is selected from the group consisting of C₁₋₆straight            chain alkyl, C₄₋₆branched chain alkyl and a group            —(CH₂)_(p)Z wherein p is 1, 2 or 3;        -   Z is hydroxy, methoxy, NHMe, phenyl or a 5- or 6-membered            non-aromatic heterocyclic group, the phenyl or heterocyclic            group being optionally substituted by one, two or three            groups independently selected from the group consisting of            halo, C₁₋₄alkyl and haloC₁₋₄alkyl;        -   R^(2′) is selected from the group consisting of methyl and            ethyl;        -   R³ is selected from the group consisting of C₁₋₆alkyl and a            group —(CH₂)_(p)Z′ wherein p is 1, 2 or 3;        -   Z′ is hydroxy, methoxy, NHMe, phenyl or a 5- or 6-membered            non-aromatic or aromatic heterocyclic group, the phenyl or            heterocyclic group being optionally substituted by one, two            or three groups independently selected from the group            consisting of halo, C₁₋₄alkyl and haloC₁₋₄alkyl; or        -   R^(2′) and R³, together with the nitrogen atom to which they            are attached, form:            -   (i) a 4 or 5-membered non-aromatic heterocyclic group,                which ring is optionally substituted by one, two or                three groups independently selected from the group                consisting of halo, hydroxy, NR¹³R¹⁴ (wherein R¹³ and                R¹⁴ are independently selected from the group consisting                of hydrogen and C₁₋₄alkyl), haloC₁₋₄alkyl, and keto; or            -   (ii) a 6-membered non-aromatic heterocyclic group, which                ring is optionally substituted by one, two or three                groups independently selected from the group consisting                of halo, hydroxy, NR¹³R¹⁴ (wherein R¹³ and R¹⁴ are                independently selected from the group consisting of                hydrogen and C₁₋₄alkyl), C₂₋₄alkyl, haloC₁₋₄alkyl and                keto;    -   b) when n and m are both simultaneously 0, R¹ is selected from        the group consisting of:        -   C₁₋₆alkoxy;        -   a monocyclic saturated or partially unsaturated 5- or            6-membered heterocyclic group, attached through a carbon            atom and optionally substituted by one, two or three groups            independently selected from the group consisting of            C₁₋₄alkyl, C(O)C₁₋₄alkyl, haloC₁₋₄alkyl, halo and keto;        -   N-linked pyrrolidinyl, optionally substituted with one, two            or three groups independently selected from the group            consisting of C₁₋₄alkyl, C(O)C₁₋₄alkyl, halo C₁₋₄alkyl, halo            and keto; and        -   oxazolyl or imidazolyl, both being optionally substituted by            C₁₋₄alkyl;    -   c) when n is 1 or 2, and m is 1, R¹ is selected from the group        consisting of C₁₋₄alkyl, benzyl, cyclopropyl, thienyl, and        NR⁹R¹⁰ wherein:        -   R⁹ is selected from the group consisting of hydrogen and            C₁₋₄alkyl, and R¹⁰ is selected from the group consisting of            C₁₋₆ straight chain alkyl, C₃₋₆cycloalkyl and —(CH₂)_(p)Z            wherein p is 1, 2 or 3;        -   Z is a phenyl or a 5- or 6-membered heterocyclic group, the            phenyl or heterocyclic group being optionally substituted by            one, two or three groups independently selected from the            group consisting of halo and C₁₋₄alkyl; or        -   R⁹ and R¹⁰, together with the nitrogen atom to which they            are attached, form a 5-membered aromatic or non-aromatic            heterocyclic group or a 6-membered non-aromatic heterocyclic            group, any of the rings being optionally substituted by one,            two or three groups independently selected from the group            consisting of C₁₋₄alkyl, halo, phenyl and (in the case of a            non-aromatic ring) keto; and    -   d) when n is 1 or 2, and m is 0, R¹ is selected from the group        consisting of cyano, hydroxy, NH₂, a C-linked 5-membered        aromatic heterocyclic group optionally substituted with one, two        or three groups independently selected from the group consisting        of C₁₋₆alkyl and C₃₋₆cycloalkyl, and NR¹¹R¹² in which:        -   R¹¹ is hydrogen and R¹² is selected from the group            consisting of SO₂C₁₋₄alkyl, SO₂C₃₋₆cycloalkyl,            C(O)C₁₋₄alkyl, and C(O)C₂₋₄alkenyl; or R¹¹ is selected from            the group consisting of C₁₋₄alkyl and C₂₋₄alkenyl, and R¹²            is selected from the group consisting of SO₂C₁₋₄alkyl,            SO₂C₃₋₆cycloalkyl, C(O)C₁₋₄alkyl, C(O)phenyl and            C(O)C₂₋₄alkenyl or        -   R¹¹ and R¹², together with the nitrogen atom to which they            are attached, form a group selected from the group            consisting of:            -   (i) a 5-membered aromatic heterocyclic group which is                optionally substituted by one or two groups                independently selected from the group consisting of                C₁₋₄alkyl, halo, haloC₁₋₄alkyl, hydroxy, C₃₋₆cycloalkyl                and C₁₋₄alkoxy; and            -   (ii) imidazolyl substituted by phenyl;            -   (iii) a 5-membered non-aromatic heterocyclic group which                is substituted by one, two or three groups independently                selected from the group consisting of keto, hydroxy and                C₁₋₄alkoxy; and            -   (iv) a 6-membered non-aromatic heterocyclic group, which                is optionally substituted by one, two or three groups                independently selected from the group consisting of                keto, hydroxy and C₁₋₄alkoxy.

In one embodiment, in formula (If) above, the compound is not a compoundin which simultaneously n=0, m=1, q=0, Y=CO and R¹ is selected from thegroup consisting of: NMe₂, pyrrolidinyl, NMeCH₂Ph, morpholinyl,piperidyl, NHEt, NEt₂, NHMe, NHCH₂-tetrahydrofuran-2-yl, NH(CH₂)₂Ph,NH(CH₂)Ph, NHtBu, NHCH₂-furan-2-yl and NH(CH₂)₃OMe.

The present invention also provides a compound of formula (I′), or asalt, or solvate thereof:

wherein:

-   -   q is 0 or 1    -   n=0, 1, or 2;    -   X is CR⁶R⁷, where R⁶ and R⁷ are each independently selected from        H, Me and F, but R⁶ and R⁷ are not both simultaneously Me; or,        when n=1, R⁶ and R⁷ together with the carbon atom to which they        are attached, form a 3-membered carbocyclic ring.    -   Y is selected from the group consisting of CO, NR⁸CO, SO, SO₂        and NR⁸SO₂    -   R⁸ is selected from H and C₁₋₄ alkyl    -   m=0 or 1,    -   and    -   a) when n is 0 and m=1, then:        -   R¹ is selected from the group consisting of C₁₋₄ alkyl, and            NR²R³ in which        -   R² is CH₃ and R³ is selected from C₁₋₆ straight chain alkyl,            C(O)C₁₋₄alkyl and —(CH₂)_(p)Z where p=1, 2 or 3;        -   Z is a phenyl or a 5- or 6-membered heterocyclic group, the            phenyl or heterocyclic group optionally being substituted            with one or more groups selected from halo, C₁₋₄alkyl and            haloC₁₋₄alkyl; or        -   R² and R³ together with the nitrogen atom to which they are            attached form a 5-membered non-aromatic heterocyclic ring,            which ring may be substituted with one or more groups            selected from halo, C₁₋₄alkyl, haloC₁₋₄alkyl, and keto;    -   b) when n and m are both simultaneously 0,        -   R¹ is a monocyclic saturated or partially unsaturated 5- or            6-membered heterocyclic ring, attached through a carbon atom            and optionally substituted with one or more groups selected            from C₁₋₄alkyl, C(O)C₁₋₄alkyl, halo C₁₋₄alkyl, halo and            keto;    -   c) when n is 1 or 2, and m is 1,        -   R¹ is selected from the group consisting of C₁₋₄ alkyl and            NR⁹R¹⁰ in which        -   R⁹ is selected from hydrogen and C₁₋₄alkyl, and R¹⁰ is            selected from C₁₋₆ straight chain alkyl, C₃₋₆cycloalkyl,            C(O)C₁₋₄alkyl and —(CH₂)_(p)Z where p=1, 2 or 3;        -   Z is a phenyl or a 5- or 6-membered heterocyclic group, the            phenyl or heterocyclic group optionally being substituted            with one or more groups selected from halo and C₁₋₄alkyl; or        -   R⁹ and R¹⁰ together with the nitrogen atom to which they are            attached form a 5-membered aromatic or non-aromatic            heterocyclic ring or a 6-membered non-aromatic heterocyclic            ring, either of which may include one or more further            heteroatoms selected from N, O or S, and may be substituted            with one or more groups selected from C₁₋₄alkyl, halo, and            (in the case of a non-aromatic ring) keto; and    -   d) when n is 1 or 2, and m is 0,        -   R¹ is selected from the group consisting of cyano, OH, NH₂            and NR¹¹R¹² in which        -   R¹¹ is selected from H and C₁₋₄alkyl, and R¹² is selected            from SO₂C₁₋₄alkyl and C(O)C₁₋₄alkyl; or        -   R¹¹ and R¹² together with the nitrogen atom to which they            are attached form a group selected from a 5-membered            aromatic heterocyclic ring, a 5-membered non-aromatic            heterocyclic ring and a 6-membered non-aromatic heterocyclic            ring, any of which may include one or more further            heteroatoms selected from N, O or S, and wherein the            5-membered aromatic heterocyclic ring is optionally            substituted with one or more groups selected from C₁₋₄alkyl,            halo, haloC₁₋₄alkyl, hydroxy and C₁₋₄alkoxy; the 5-membered            non-aromatic heterocyclic ring is substituted with one or            more groups selected from keto, hydroxy and C₁₋₄alkoxy; and            the 6-membered non-aromatic heterocyclic ring is optionally            substituted with one or more groups selected from keto,            hydroxy and C₁₋₄alkoxy;            with the proviso that the compound is not:    -   the compound in which simultaneously n=0, m=0, q=0, and R¹=NH₂.    -   a compound in which simultaneously n=0, m=1, q=0, Y=CO and R¹ is        selected from NMeCH₂Ph, piperidinyl, pyrrolidinyl, NH₂,        N-methylpiperizinyl, NMe₂ and morpholinyl.

Any statements above regarding embodiments of compounds of any offormula (I), (Ia), (Ib), (Ic), (Id), (Ie) and (If) above apply equallyto each other and to compounds of formula (A), (B) and (B′).

For the avoidance of doubt, unless otherwise indicated, the termsubstituted means substituted by one or more defined groups. In the casewhere groups may be selected from a number of alternative groups, theselected groups may be the same or different.

For the avoidance of doubt, the term independently means that where morethan one substituent is selected from a number of possible substituents,those substituents may be the same or different.

It will be appreciated that the present invention is intended to includecompounds having any combination of the groups listed hereinbefore.

In one embodiment the salt or solvate of the compound of formula (I) isa pharmaceutically acceptable salt or solvate. In one embodiment, theinvention provides a compound of formula (I), a pharmaceuticallyacceptable salt or solvate thereof.

As used herein, the term “salt” refers to any salt of a compoundaccording to the present invention prepared from an inorganic or organicacid or base, quaternary ammonium salts and internally formed salts.Pharmaceutically acceptable salts are particularly suitable for medicalapplications because of their greater aqueous solubility relative to theparent compounds. Such salts must clearly have a pharmaceuticallyacceptable anion or cation. Suitably pharmaceutically acceptable saltsof the compounds of the present invention include acid addition saltsformed with inorganic acids such as hydrochloric, hydrobromic,hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, andwith organic acids, such as tartaric, acetic, trifluoroacetic, citric,malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic,maleic, succinic, (1S)-(−)-10-camphorsulphonic,(1S)-(+)-10-camphorsulphonic, isothionic, mucic, gentisic, isonicotinic,saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic,salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic,ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonicand arylsulfonic, for example naphthalene-1,5-disulphonic,naphthalene-1,3-disulphonic, benzenesulfonic, and p-toluenesulfonic,acids; base addition salts formed with alkali metals and alkaline earthmetals and organic bases such as N,N-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine(N-methylglucamine), lysine and procaine; and internally formed salts.Salts having a non-pharmaceutically acceptable anion or cation arewithin the scope of the invention as useful intermediates for thepreparation of pharmaceutically acceptable salts and/or for use innon-therapeutic, for example, in vitro, situations. The salts may haveany suitable stoichiometry. For example, a salt may have 1:1 or 2:1stoichiometry. Non-integral stoichiometry ratios are also possible.

Furthermore, some of the crystalline forms of the compounds of formula(I) may exist as polymorphs, which are included in the presentinvention.

Furthermore, some of the crystalline forms of the compounds of structure(I) may exist as polymorphs, which are included in the presentinvention. Some of the compounds of this invention may be crystallisedor recrystallised from solvents such as aqueous and organic solvents. Insuch cases solvates may be formed. This invention includes within itsscope stoichiometric solvates as well as compounds containing variableamounts of solvent, where non-stoichiometric solvates may be produced byprocesses such as lyophilisation. In one embodiment, the compounds ofthe present invention are provided in the form of stoichiometric andnon-stoichiometric hydrates.

It will be appreciated by those skilled in the art that certainprotected derivatives of compounds of formula (I), which may be madeprior to a final deprotection stage, may not possess pharmacologicalactivity as such, but may, in certain instances, be administered orallyor parenterally and thereafter metabolised in the body to form compoundsof the invention which are pharmacologically active. Such derivativesmay therefore be described as “prodrugs”. Further, certain compounds ofthe invention may be administered as prodrugs. Examples of pro-drugforms for certain compounds of the present invention are described inDrugs of Today, Volume 19, Number 9, 1983, pp 499-538 and in Topics inChemistry, Chapter 31, pp 306-316 and in “Design of Prodrugs” by H.Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documentsare incorporated herein by reference). It will further be appreciated bythose skilled in the art, that certain moieties, known to those skilledin the art as “pro-moieties”, for example as described by H. Bundgaardin “Design of Prodrugs” (the disclosure in which document isincorporated herein by reference) may be placed on appropriatefunctionalities when such functionalities are present within compoundsof the invention. Examples of prodrugs for certain compounds of theinvention include: esters, carbonate esters, hemi-esters, phosphateesters, nitro esters, sulfate esters, sulfoxides, amides, carbamates,azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.

Certain compounds of formula (I) are capable of existing instereoisomeric forms (e.g. geometric (or “cis-trans”) isomers,diastereomers and enantiomers) and the invention extends to each ofthese stereoisomeric forms and to mixtures thereof including racemates.The different stereoisomeric forms may be separated one from the otherby the usual methods, or any given isomer may be obtained bystereospecific or asymmetric synthesis. The invention also extends toany tautomeric forms and mixtures thereof. The present inventionincludes within its scope all such isomers, including mixtures. It willbe appreciated, in common with most biologically active molecules thatthe level of biological activity may vary between the enantiomers of agiven molecule.

In one embodiment a compound of the invention in chiral form has atleast 80% e.e. In another embodiment, a compound of the invention inchiral form has at least 90% e.e., for example at least 95% e.e. Inanother embodiment the isomers correspond to at least 98% e.e, forexample at least 99% e.e.

Since the compounds of the invention are intended for use inpharmaceutical compositions it will readily be understood that they areeach optionally provided in substantially pure form, for example atleast 60% pure, for example at least 75% pure or at least 85%, or atleast 98% pure (% are on a weight for weight basis). Impure preparationsof the compounds may be used for preparing the more pure forms used inthe pharmaceutical compositions; these less pure preparations of thecompounds should contain at least 1%, or at least 5% or from 10 to 59%of a compound of the invention.

Compounds of the invention may be prepared in a variety of ways. Theseprocesses form further aspects of the invention.

The present invention also provides a process for the manufacture of acompound of formula (I) or a salt or solvate thereof, which processcomprises coupling a compound of formula (II):

wherein X′ is a leaving group and X, Y, q, m, n and R¹ are as definedfor formula (I), with3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole:

and thereafter optionally:

-   -   removing any protecting groups; and/or    -   converting a compound of formula (I) or a salt or solvate        thereof to another compound of formula (I) or a salt or solvate        thereof.

In the above reaction, for compounds of formula (I) wherein q is 0, X′may be for example a halogen such as bromine or iodine. Typical reactionconditions for compounds of formula (I) wherein q is 0 comprise heatinga compound of formula (II),3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole, a base (such aspotassium carbonate or cesium carbonate), copper (I) iodide or copper(I) oxide with N,N-dimethylglycine at 190 degc in a microwave reactor orwith conventional heating at 130 degc in dimethylsulfoxide ortrans-1,2-diaminocyclohexane in 1,4-dioxane at 180 degc in a microwavereactor, or (1R,2R)-N,N′-dimethyl-1,2-cyclohexanediamine in toluene at130 degc in a microwave reactor. In one embodiment, (X)_(n)(Y)_(m)R¹ isan acid, amide, ester, sulphonamide, ketone, urea, sulfone, alcohol,nitrile or a heterocyclic group.3-(Trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole is commerciallyavailable. Compounds of formula (II) are commercially available or maybe prepared as described herein or by conventional chemistry.

In the above reaction, for compounds of formula (I) wherein q is 1, X′may be for example a halogen such as bromine. Typical reactionconditions for compounds of formula (I) wherein q is 1 comprise stirringa mixture of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole and acompound of formula (II) in dimethylformamide with potassium carbonateat room temperature for 16 hours. Compounds of formula (II) arecommercially available or may be prepared as described herein or byconventional chemistry.3-(Trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole) is commerciallyavailable.

A compound of formula (XIV) (ie a compound of formula (II) wherein X, nand R¹ are as defined for formula (I)) can be prepared from a compoundof formula (XIII) (wherein X, n and R¹ are as defined for formula (I))by iodination according to reaction scheme 2. Typical conditionscomprise heating a mixture of a compound of formula (XIII), iodine,periodic acid, water and concentrated sulphuric acid in acetic acid at60 degc for approximately 6 hours. In one embodiment, X is a methyleneor methyl substituted methylene, and R¹ is NR⁹R¹⁰ wherein R⁹ and R¹⁰ arealiphatic and may be the same or different, or are linked to form aring. Compounds of formula (XIII) are commercially available or may beprepared using conventional chemistry.

A compound of formula (XVII), which is useful for the preparation of acompound of formula (II), can be prepared from a compound of formula(XV) by acylation or sulphonylation using a reagent of formula (XVI)according to reaction scheme 3. Typical conditions comprise addition ofreagent (XVI) to a cooled solution of (XV) in dichloromethane in thepresence of a suitable base such as triethylamine or1,8-diazabicyclo[5.4.0]undec-7-ene. In one embodiment, X is a carbonylor sulphonyl, R/Ar is aliphatic or aromatic, and R′ and R″ are aliphatic(or one may be hydrogen) and may be the same or different, or are linkedto form a ring. Compounds of formula (XV) are commercially available.Compounds of formula (XVI) are commercially available or may be preparedanalogously to as set out above in Scheme 11 below.

A compound of formula (XIX), which is useful for the preparation of acompound of formula (II), can be prepared by coupling a compound offormula (XVIII) with a secondary amine according to reaction scheme 4.Typical coupling conditions comprise treatment of a compound of formula(XVII) with 1,1′-carbonyldiimidazole in dichloromethane, followed byaddition of the secondary amine after a short stirring period at ambienttemperature (a base such as triethylamine or diisopropylamine is alsoadded should the amine be available as an acid salt). In one embodiment,R/Ar is aliphatic or aromatic, and R′ and R″ are aliphatic and may bethe same or different, or are linked to form a ring. Compounds offormula (XVIII) are commercially available.

A compound of formula (XXI), which is useful for the preparation of acompound of formula (II), can be prepared by alkylation of a secondaryamide or urea of formula (XX) with an alkylhalide according to reactionscheme 5. Typical alkylation conditions comprise treatment of a compoundof formula (XX) with a suitable base such as sodium hydride (availableas a 60% suspension in mineral oil) in dimethylformamide, followed bythe addition of the alkylating agent. In one embodiment, R′ and R″ arealiphatic (in the case of amides) and may be the same or different, orare linked to form a ring, or R′ is aromatic and R″ is an amineconnected through the nitrogen (in the case of ureas).

A compound of formula (XXXVI), which is useful for the preparation of acompound of formula (II), can be prepared by acylation of a secondaryamine with a compound of formula (XXXV) according to reaction scheme 6.Typical reaction conditions comprise addition of the secondary amine toa solution of a compound of formula (XXXV) and a suitable base such astriethylamine and stirring at room temperature. In one embodiment, R′and R″ are aliphatic and may be the same or different, or are linked toform a ring, and R/Ar is aliphatic or aromatic. Compounds of formula(XXXV) are commercially available.

A compound of formula (XLII), which is useful for the preparation of acompound of formula (II), can be prepared by acylation then alkylationof a compound of formula (XL) using 4-chlorobutyryl chloride or3-chloropropanesulfonyl chloride according to reaction scheme 7. Typicalconditions comprise treating a solution of a compound of formula (XL)and a suitable base such as triethylamine in dimethylformamide with4-chlorobutyryl chloride or 3-chloropropanesulfonyl chloride, followedby the addition of excess sodium hydride (60% suspension in mineral oil)and stirring at room temperature until complete cyclisation. In oneembodiment, R/Ar is aliphatic or aromatic, and X is a carbonyl orsulfonyl. Compounds of formula (XL) are commercially available.Compounds of formula (XLI) are commercially available.

A compound of formula (IV) (ie a compound of formula (I) in which n=0, 1or 2, X=CH₂, Y=CO, m=1 and R¹=NR²R³ or R¹=NR⁹R¹⁰ wherein R², R³, R⁹ andR¹⁰ are as defined for formula (I)) can be prepared by coupling acompound of formula (V) with a secondary amine according to reactionscheme 8. Typical coupling conditions comprise treatment of a compoundof formula (V) with 1,1′-carbonyldiimidazole in dichloromethane,followed by addition of the secondary amine after a 15 minute stirringperiod at ambient temperature. In one embodiment, R² and R³, or R⁹ andR¹⁰, are aliphatic (or one is hydrogen) and may be the same ordifferent, or are linked to form a ring.

A compound of formula (V), wherein q and n are as defined for formula(I), can be prepared from an ester of formula (X) (wherein q and n areas defined for formula (I) and R=alkyl for example C₁₋₆alkyl) accordingto reaction Scheme 9. Typical reaction conditions comprise heating asolution of the ester of formula (X) and sodium hydroxide in a 1:1 mixof water and ethanol at reflux for 1 hour. Compounds of formula (X) canbe prepared in a manner similar to that described above for compounds offormula (I), ie reacting a compound of formula (II) with3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole).

A compound of formula (VI) (ie a compound of formula (I) in which q=0,X=CH₂, n=1 or 2, Y=NR⁸CO, m=1 and R¹ and R⁸ are as defined for formula(I)) can be prepared by acylation of a secondary amide of formula (VIII)with an alkylhalide compound of formula (VII) according to reactionscheme 10. Typical alkylation conditions comprise treatment of acompound of formula (VIII) with a suitable base such as sodium hydride(available as a 60% suspension in mineral oil) in dimethylformamide,followed by the addition of the alkylating agent (VII). In oneembodiment, R¹ and R⁸ are aliphatic and may be the same or different, orare linked to form a ring. Compounds of formula (VIII) are commerciallyavailable.

A compound of formula (VII) can be prepared from a benzylic alcohol offormula (IX) according to reaction scheme 11. Typical reactionconditions comprise treatment of a compound of formula (IX) indichloromethane with a suitable base such as triethylamine, followed bythe addition of methanesulfonyl chloride and stirring at roomtemperature for 18 h hours. Compounds of formula (IX) can be prepared ina manner similar to that described above for compounds of formula (I),ie reacting a compound of formula (II) with3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole).

A compound of formula (XII) (ie a compound of formula (I) in which q=1,n=0, Y=CO, m=1 and R¹=NR²R³ wherein R² and R³ together with the nitrogenatom to which they are attached form a 4, 5 or 6-membered non-aromaticheterocyclic group as defined for formula (I) and indicated as “G” inScheme 12 below) can be prepared by alkylation of3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole with an alkylhalidecompound of formula (XI) according to reaction scheme 12. Typicalalkylation conditions comprise heating a mixture of3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole and (XI) indimethylformamide with potassium carbonate at 140 degc in a microwavereactor for 10 minutes. Compounds of formula (XI) are commerciallyavailable or may be prepared from the corresponding acid in a mannersimilar to that set out in Scheme 8.

A compound of formula (XXIII) can be prepared from a benzonitrile offormula (XXII) according to reaction scheme 13. Typical reactionconditions comprise treatment of a solution of lithium aluminium hydridein tetrahydrofuran with a compound of formula (XXII) in tetrahydrofuranwith cooling, followed by stirring at room temperature for 1.5 h hours.Compounds of formula (XXII) can be prepared in a manner similar to thatdescribed above for compounds of formula (I), ie reacting a compound offormula (II) with 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole).

A compound of formula (XXVI) (i.e. a compound of formula (I) where n=0,m=1, Y=CO and R¹=NMe(CH₂)p-Ar wherein p is 1, 2 or 3 and Ar is phenyl or5- or 6-membered heterocyclic group, as defined for formula (I)) can beprepared by coupling a compound of formula (XXIV) with a secondary amineaccording to reaction scheme 14. Typical coupling conditions comprisetreatment of polymer supported1-ethyl-3-(dimethylaminopropyl)carbodiimide with a solution of1-hydroxy-7-azabezotriazole in tetrahydrofuran:dichloromethane (1:1)followed by the addition of the benzoic acid (XXIV) inN-methyl-2-pyrrolidinone:tetrahydrofuran (1:3), followed by the additionof the amine (XXV) in dichloromethane and allowed to mix for 60 hours.In one embodiment, Ar is aromatic or heterocyclic and n is 1, 2 or 3.Compounds of formula (XXIV) can be prepared in a manner similar to thatdescribed above for compounds of formula (I), ie reacting a compound offormula (II) with 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole).Compounds of formula (XXV) are commercially available. Compounds offormula (XXIV) can be prepared in a manner similar to that describedabove for compounds of formula (I).

A compound of formula (XXVII) (i.e. a compound of formula (I) whereinn=1 or 2, m=0, X=CH₂ and R¹=NHR^(12′) wherein R^(12′) is SO₂C₁₋₄alkyl,SO₂C₃₋₆cycloalkyl, C(O)C₁₋₄alkyl, C(O)phenyl or C(O)C₂₋₄alkenyl) can beprepared from a compound of formula (XXIII) by acylation orsulphonylation using a reagent of formula (XVI) according to reactionscheme 15. Typical conditions comprise addition of reagent (XVI) to asolution of (XXIII) in dichloromethane or 5-10% dimethylformamide indichloromethane in the presence of a suitable base such astriethylamine. Compounds of formula (XVI) are commercially available.

A compound of formula (XXX) (ie a compound of formula (I) wherein q=0,n=1, m=1, Y=CO, X=CR⁶R⁷ wherein R⁶ is fluorine and R⁷ is hydrogen orfluorine, R¹=NR⁹R¹⁰ wherein R⁹ and R¹⁰ form a 5-membered aromatic ornon-aromatic heterocyclic group or a 6-membered non-aromaticheterocyclic group, as defined for formula (I)) can be prepared from acompound of formula (XXVIII) by fluorination using a reagent of formula(XXIX) according to reaction scheme 16. Typical conditions compriseaddition of a tetrahydrofuran solution of a compound of formula (XXVIII)to a solution of lithium diisopropylamide in tetrahydrofuran at −78 degcfollowed 1 hour later by the addition of the fluorinating agent (XXIX)in tetrahydrofuran, then stirring at ambient temperature, giving a mixof R═H and R═F. The compound of formula (XXVIII) can be prepared in amanner similar to that described above for compounds of formula (I), iereacting a compound of formula (II) with3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole). The compound offormula (XXIX) is commercially available.

A compound of formula (XXXIV) (ie a compound of formula (I) wherein q is0 or 1, m and n are both 0 and R¹ is optionally substituted N-linkedpyrrolidinyl substituted with one keto) can be prepared by acylationthen alkylation of a compound of formula (XXXIII) using 4-chlorobutyrylchloride according to reaction scheme 17. Typical conditions comprisetreating a solution of a compound of formula (XXXIII) and a suitablebase such as diisopropylethylamine in dimethylformamide with4-chlorobutyryl chloride, followed by the addition of excess sodiumhydride (60% suspension in mineral oil) and stirring at roomtemperature.

A compound of formula (XXXIII) can be prepared by reduction of thecompound of formula (XXXII) using sodium borohydride according to scheme18. Typical conditions comprise addition of a compound of formula(XXXII) in methanol to a suspension of 10% palladium on charcoal andsodium borohydride in water and stirring at room temperature for 1 hour.

A compound of formula (XXXIX) (ie a compound of formula (I) wherein m is0, n=1 or 2, R¹ is 1,2,4-oxadiazol-5-yl and R is C₁₋₆alkyl orC₃₋₆cycloalkyl) can be prepared upon reaction of a compound of formula(XXXVII) with an amidoxime of formula (XXXVIII) according to reactionscheme 19. Typical conditions comprise addition of1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride to a slurry ofthe acid (XXXVII) and 1-hydroxybenzotriazole in acetonitrile, followedby the addition of the appropriate amidoxime after 30 minutes, and thenheating at reflux. Compounds of formula (XXXVIII) are commerciallyavailable. Compounds of formula (XXXVII) can be prepared in a mannersimilar to that described above for compounds of formula (V) in Scheme9.

A compound of formula (XLV) (ie a compound of formula (I) wherein q=0,n=0, m=1, Y=CO and R¹ is a C-linked 5-membered aromatic heterocyclicgroup optionally substituted by methyl) can be prepared in 3 stages from3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole, 4-bromoiodobenzeneand a compound of formula (XLIV) according to reaction scheme 20.Typical reaction conditions comprise heating compound A with4-bromoiodobenzene in the presence of a base (such as potassiumcarbonate), copper (I) iodide and N,N-dimethylglycine with conventionalheating at 130 degC in dimethylsulfoxide. The product is isolated thentreated with n-butyllithium in tetrahydrofuran at −78 degC, followed bythe treatment with a compound of formula (XLIV).3-(Trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole and bromoiodobenzeneare commercially available.

A compound of formula (XLIV) can be prepared by the acylation of acompound of formula (XLIII) (wherein R1′ is a C-linked 5-memberedaromatic heterocyclic group optionally substituted with methyl) withN,O-dimethylhydroxylamine hydrochloride according to reaction scheme 21.Typical acylation conditions comprise the addition of HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) to a solution of the compound of formula (XLIII),with N,O-dimethylhydroxylamine hydrochloride and diisopropylamine(DIPEA) in dimethylformamide and stirring at room temperature for 17hours. The compound of formula (XLIII) is commercially available.

A compound of formula (XLVI) (wherein q is as defined for formula (I),n=0, m=1, Y=NHCO and R²R³ form a 4, 5 or 6-membered non-aromaticheterocyclic group optionally substituted as defined for formula (I)),can be prepared from a compound of formula (XXIV) via a Curtiusrearrangement and subsequent reaction with a compound HNR²R³, accordingto reaction scheme 22. For example, HNR²R³ may be pyrrolidine. Typicalreaction conditions comprise addition of diphenylphosphoryl azide (DPPA)to a mixture of a compound of formula (XXIV) and diisopropylethylamine(DIPEA) in 1,4-dioxane. After 2 hours of stirring at reflux the mix istreated with the HNR²R³ compound, and reflux continued for a furtherhour. Compounds of formula (XXIV) can be prepared in a manner similar tothat described above for compounds of formula (I), ie reacting acompound of formula (II) with3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole).

A compound of formula (XLVIII) (wherein q is as defined for formula (I),n=1 or 2, m=0 and R¹ is a group NR¹¹R¹² wherein R¹¹ and R¹² form a5-membered aromatic heterocyclic group optionally substituted by one ortwo groups independently selected from the group consisting ofC₁₋₄alkyl, halo, haloC₁₋₄alkyl, hydroxy, C₃₋₆cycloalkyl and C₁₋₄alkoxy;or imidazolyl substituted by phenyl, or a 5- or 6-membered non-aromaticheterocyclic group which is substituted by at least one keto, andoptionally by one or two other groups independently selected from thegroup consisting of keto, hydroxy and C₁₋₄alkoxy) can be prepared by thealkylation of a heterocyclic group of formula (XLVII) (wherein R¹¹ andR¹² are as defined for formula (XLVIII)), with the benzyl chloridecompound of formula (VII) according to reaction scheme 23. Typicalalkylation conditions comprise treatment of a compound of formula(XLVII) with a suitable base such as sodium hydride (available as a 60%suspension in mineral oil) in dimethylformamide, followed by theaddition of the alkylating agent (VII). In one embodiment, NR¹¹R¹² is animidazolyl, triazolyl or pyrazolyl derivative. Compounds of formula(XLVII) are commercially available. The compound of formula (VII) can beprepared in a manner similar to that described above in Scheme 11.

Further details for the preparation of compounds of formula (I) arefound in the Examples section hereinafter.

The compounds of the invention may be prepared singly or as compoundlibraries comprising at least 2, for example 5 to 1,000 compounds, forexample 10 to 100 compounds. Libraries of compounds of the invention maybe prepared by a combinatorial ‘split and mix’ approach or by multipleparallel synthesis using either solution phase or solid phase chemistry,by procedures known to those skilled in the art. Thus according to afurther aspect there is provided a compound library comprising at least2 compounds of the invention.

The compounds of the present invention potentiate the AMPA receptor.Compounds which potentiate the AMPA receptor are potentially useful fortreating diseases and conditions which are mediated by the potentiationof the glutamate receptor.

Thus the present invention provides a compound of formula (I) or a saltor solvate thereof, excluding4-methyl-N-[4-[4,5,6,7-tetrahydro-3-(trifluoromethyl)-1H-indazol-1-yl]phenyl]-1,2,3-thiadiazole-5-carboxamideand salts thereof for use as a medicament.

In one embodiment, the compound of formula (I) is a compound selectedfrom the group consisting of formula (Ia) (excluding4-methyl-N-[4-[4,5,6,7-tetrahydro-3-(trifluoromethyl)-1H-indazol-1-yl]phenyl]-1,2,3-thiadiazole-5-carboxamideand salts thereof), (Ib), (Ic), (Id), (Ie) and (If).

In one embodiment, there is provided a compound of formula (Ig) or asalt or solvate thereof for use in medicine:

wherein R′ and R″, together with the nitrogen atom to which they areattached, form a pyrrolidinyl or morpholinyl.

The present invention also provides a compound of formula (Ih) for usein medicine:

in which R¹ is a group NR²R³ in which R² and R³ together with thenitrogen atom to which they are attached form a 5-membered non-aromaticheterocyclic ring, which may be substituted with one or more groupsselected from halo, C₁₋₄alkyl, haloC₁₋₄alkyl, and keto. In oneembodiment, R² and R³ together with the nitrogen atom to which they areattached form a pyrrolidinyl ring, which may be substituted with one ormore groups selected from halo, C₁₋₄alkyl, haloC₁₋₄alkyl and keto.

The present invention also provides a salt or a solvate of a compound offormula (Ih) as defined above for use in medicine.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I) or a salt or solvate thereof,excluding4-methyl-N-[4-[4,5,6,7-tetrahydro-3-(trifluoromethyl)-1H-indazol-1-yl]phenyl]-1,2,3-thiadiazole-5-carboxamideand salts thereof, and at least one carrier, diluent or excipient.

In one embodiment, the compound of formula (I) is selected from thegroup consisting of a compound of formula (Ia) (excluding4-methyl-N-[4-[4,5,6,7-tetrahydro-3-(trifluoromethyl)-1H-indazol-1-yl]phenyl]-1,2,3-thiadiazole-5-carboxamideand salts thereof), (Ib), (Ic), (Id), (Ie), (If), (Ig) and (Ih).

The present invention also provides a compound of formula (II) or a saltor solvate thereof for use in the treatment of a disease or a conditionwhich is mediated by the glutamate receptor:

wherein:

-   -   q is 0 or 1;    -   n is 0, 1, or 2;    -   X is CR⁶R⁷, where R⁶ and R⁷ are each independently selected from        the group consisting of hydrogen, methyl and fluoro, but R⁶ and        R⁷ are not both simultaneously methyl; or, when n is 1, R⁶ and        R⁷ together with the carbon atom to which they are attached,        form a 3-membered carbocyclic ring;    -   Y is selected from the group consisting of CO, NR⁸CO, SO, SO₂        and NR⁸SO₂;    -   R⁸ is selected from the group consisting of hydrogen,        C₂₋₄alkenyl and C₁₋₄alkyl;    -   m is 0 or 1; and    -   a) when n is 0 and m=1, then R¹ is selected from the group        consisting of (i) C₁₋₄alkyl, (ii) a C-linked 5-membered aromatic        heterocyclic group optionally substituted with methyl, (iii)        NHR² and (iv) NR^(2′)R³, wherein:        -   R² is selected from the group consisting of C₁₋₆straight            chain alkyl, C₄₋₆branched chain alkyl and a group            —(CH₂)_(p)Z wherein p is 1, 2 or 3;        -   Z is hydroxy, methoxy, NHMe, phenyl or a 5- or 6-membered            non-aromatic heterocyclic group, the phenyl or heterocyclic            group being optionally substituted by one, two or three            groups independently selected from the group consisting of            halo, C₁₋₄alkyl and haloC₁₋₄alkyl; wherein when Y is CO, R²            is not (CH₂)₂pyrrolidinyl;        -   R^(2′) is selected from the group consisting of methyl and            ethyl;        -   R³ is selected from the group consisting of C₁₋₆alkyl and a            group —(CH₂)_(p)Z′ wherein p is 1, 2 or 3;        -   Z′ is hydroxy, methoxy, NHMe, phenyl or a 5- or 6-membered            non-aromatic or aromatic heterocyclic group, the phenyl or            heterocyclic group being optionally substituted by one, two            or three groups independently selected from the group            consisting of halo, C₁₋₄alkyl and haloC₁₋₄alkyl; or        -   R^(2′) and R³, together with the nitrogen atom to which they            are attached, form:            -   (i) a 4 or 5-membered non-aromatic heterocyclic group,                which ring is optionally substituted by one, two or                three groups independently selected from the group                consisting of halo, hydroxy, NR¹³R¹⁴ (wherein R¹³ and                R¹⁴ are independently selected from the group consisting                of hydrogen and C₁₋₄alkyl), haloC₁₋₄alkyl, and keto; or            -   (ii) a 6-membered non-aromatic heterocyclic group, which                ring is optionally substituted by one, two or three                groups independently selected from the group consisting                of halo, hydroxy, NR¹³R¹⁴ (wherein R¹³ and R¹⁴ are                independently selected from the group consisting of                hydrogen and C₁₋₄alkyl), C₂₋₄alkyl, haloC₁₋₄alkyl and                keto;    -   b) when n and m are both simultaneously 0, R¹ is selected from        the group consisting of:        -   C₁₋₆alkoxy;        -   a monocyclic saturated or partially unsaturated 5- or            6-membered heterocyclic group, attached through a carbon            atom and optionally substituted by one, two or three groups            independently selected from the group consisting of            C₁₋₄alkyl, C(O)C₁₋₄alkyl, haloC₁₋₄alkyl, halo and keto;        -   N-linked pyrrolidinyl, optionally substituted with one, two            or three groups independently selected from the group            consisting of C₁₋₄alkyl, C(O)C₁₋₄alkyl, halo C₁₋₄alkyl, halo            and keto; and        -   oxazolyl or imidazolyl, both being optionally substituted by            C₁₋₄alkyl;    -   c) when n is 1 or 2, and m is 1, R¹ is selected from the group        consisting of C₁₋₄alkyl, benzyl, cyclopropyl, thienyl, and        NR⁹R¹⁰ wherein:        -   R⁹ is selected from the group consisting of hydrogen and            C₁₋₄alkyl, and R¹⁰ is selected from the group consisting of            C₁₋₆ straight chain alkyl, C₃₋₆cycloalkyl and —(CH₂)_(p)Z            wherein p is 1, 2 or 3;        -   Z is a phenyl or a 5- or 6-membered heterocyclic group, the            phenyl or heterocyclic group being optionally substituted by            one, two or three groups independently selected from the            group consisting of halo and C₁₋₄alkyl; or        -   R⁹ and R¹⁰, together with the nitrogen atom to which they            are attached, form a 5-membered aromatic or non-aromatic            heterocyclic group or a 6-membered non-aromatic heterocyclic            group, any of the rings being optionally substituted by one,            two or three groups independently selected from the group            consisting of C₁₋₄alkyl, halo, phenyl and (in the case of a            non-aromatic ring) keto; and    -   d) when n is 1 or 2, and m is 0, R¹ is selected from the group        consisting of cyano, hydroxy, NH₂, a C-linked 5-membered        aromatic heterocyclic group optionally substituted with one, two        or three groups independently selected from the group consisting        of C₁₋₆alkyl and C₃₋₆cycloalkyl, and NR¹¹R¹² in which:        -   R¹¹ is hydrogen and R¹² is selected from the group            consisting of SO₂C₁₋₄alkyl, SO₂C₃₋₆cycloalkyl,            C(O)C₁₋₄alkyl, and C(O)C₂₋₄alkenyl; or R¹¹ is selected from            the group consisting of C₁₋₄alkyl and C₂₋₄alkenyl, and R¹²            is selected from the group consisting of SO₂C₁₋₄alkyl,            SO₂C₃₋₆cycloalkyl, C(O)C₁₋₄alkyl, C(O)phenyl and            C(O)C₂₋₄alkenyl or        -   R¹¹ and R¹², together with the nitrogen atom to which they            are attached, form a group selected from the group            consisting of:            -   (i) a 5-membered aromatic heterocyclic group which is                optionally substituted by one or two groups                independently selected from the group consisting of                C₁₋₄alkyl, halo, haloC₁₋₄alkyl, hydroxy, C₃₋₆cycloalkyl                and C₁₋₄alkoxy; and            -   (ii) imidazolyl substituted by phenyl;            -   (iii) a 5-membered non-aromatic heterocyclic group which                is substituted by one, two or three groups independently                selected from the group consisting of keto, hydroxy and                C₁₋₄alkoxy; and            -   (iv) a 6-membered non-aromatic heterocyclic group, which                is optionally substituted by one, two or three groups                independently selected from the group consisting of                keto, hydroxy and C₁₋₄alkoxy.

The present invention also provides a compound of formula (J) or a saltor solvate thereof for use as a medicament:

wherein:

-   -   q is 0 or 1    -   n=0, 1, or 2;    -   X is CR⁶R⁷, where R⁶ and R⁷ are each independently selected from        H, Me and F, but R⁶ and R⁷ are not both simultaneously Me; or,        when n=1, R⁶ and R⁷ together with the carbon atom to which they        are attached, form a 3-membered carbocyclic ring.    -   Y is selected from the group consisting of CO, NR⁸CO, SO, SO₂        and NR⁸SO₂    -   R⁸ is selected from H and C₁₋₄ alkyl    -   m=0 or 1    -   and    -   a) when n is 0 and m=1, then:        -   R¹ is selected from the group consisting of C₁₋₄ alkyl, and            NR²R³ in which:            -   R² is CH₃ and R³ is selected from C₁₋₆ straight chain                alkyl, C(O)C₁₋₄alkyl and —(CH₂)_(p)Z where p=1, 2 or 3;            -   Z is a phenyl or a 5- or 6-membered heterocyclic group,                the phenyl or heterocyclic group optionally being                substituted with one or more groups selected from halo,                C₁₋₄alkyl and haloC₁₋₄alkyl; or            -   R² and R³ together with the nitrogen atom to which they                are attached form a 5-membered non-aromatic heterocyclic                ring, which ring may be substituted with one or more                groups selected from halo, C₁₋₄alkyl, haloC₁₋₄alkyl, and                keto;    -   b) when n and m are both simultaneously 0,        -   R¹ is a monocyclic saturated or partially unsaturated 5- or            6-membered heterocyclic ring, attached through a carbon atom            and optionally substituted with one or more groups selected            from C₁₋₄alkyl, C(O)C₁₋₄alkyl, halo C₁₋₄alkyl, halo and            keto;    -   c) when n is 1 or 2, and m is 1,        -   R¹ is selected from the group consisting of C₁₋₄ alkyl and            NR⁹R¹⁰ in which:            -   R⁹ is selected from hydrogen and C₁₋₄alkyl, and R¹⁰ is                selected from C₁₋₆ straight chain alkyl, C₃₋₆cycloalkyl,                C(O)C₁₋₄alkyl and —(CH₂)_(p)Z where p=1, 2 or 3;            -   Z is a phenyl or a 5- or 6-membered heterocyclic group,                the phenyl or heterocyclic group optionally being                substituted with one or more groups selected from halo                and C₁₋₄alkyl; or            -   R⁹ and R¹⁰ together with the nitrogen atom to which they                are attached form a 5-membered aromatic or non-aromatic                heterocyclic ring or a 6-membered non-aromatic                heterocyclic ring, either of which may include one or                more further heteroatoms selected from N, O or S, and                may be substituted with one or more groups selected from                C₁₋₄alkyl, halo, and (in the case of a non-aromatic                ring) keto; and    -   d) when n is 1 or 2, and m is 0,        -   R¹ is selected from the group consisting of cyano, OH, NH₂            and NR¹¹R¹² in which        -   R¹¹ is selected from H and C₁₋₄alkyl, and R¹² is selected            from SO₂C₁₋₄alkyl and C(O)C₁₋₄alkyl; or        -   R¹¹ and R¹² together with the nitrogen atom to which they            are attached form a group selected from a 5-membered            aromatic heterocyclic ring, a 5-membered non-aromatic            heterocyclic ring and a 6-membered non-aromatic heterocyclic            ring, any of which may include one or more further            heteroatoms selected from N, O or S, and wherein the            5-membered aromatic heterocyclic ring is optionally            substituted with one or more groups selected from C₁₋₄alkyl,            halo, haloC₁₋₄alkyl, hydroxy and C₁₋₄alkoxy; the 5-membered            non-aromatic heterocyclic ring is substituted with one or            more groups selected from keto, hydroxy and C₁₋₄alkoxy; and            the 6-membered non-aromatic heterocyclic ring is optionally            substituted with one or more groups selected from keto,            hydroxy and C₁₋₄alkoxy.

Any statements above regarding embodiments of compounds of any offormula (I), (A), (Ia), (Ib), (Ic), (Id), (Ie), (If) above apply tocompounds of formula (Ig), formula (Ih) and formula (Ii).

Examples of compounds for use as a medicament as described herein, orfor a composition as described herein, or for use in the treatment of adisease or a condition which is mediated by the glutamate receptor asdescribed herein, include:

-   1.    N,N-dimethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 1)-   2.    1-[4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 2)-   3.    N-methyl-N-(phenylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 3)-   4.    N-ethyl-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 4)-   5.    N-butyl-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 5)-   6.    N-methyl-N-(2-phenylethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 6)-   7.    N,N-dimethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide    (Example 7)-   8.    1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}ethanone    (Example 8)-   9.    1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-1-propanone    (Example 9)-   10.    1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 10)-   11.    1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-2-propanone    (Example 11)-   12.    N,N-dimethyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 12)-   13.    1-{4-[2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 13)-   14.    N-ethyl-N-methyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 14)-   15.    N-methyl-N-(phenylmethyl)-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 15)-   16.    N-butyl-N-methyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 16)-   17. N-methyl-N-(2-phenylethyl)-2-{4-[3-(trifluoro    methyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide (Example    17)-   18.    1-{[4-(1-pyrrolidinylcarbonyl)phenyl]methyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 18)-   19.    1-{4-[1-methyl-2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 19)-   20.    N,N-dimethyl-3-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}propanamide    (Example 20)-   21.    1-{4-[3-oxo-3-(1-pyrrolidinyl)propyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 21)-   22.    1-{4-[1-(1-pyrrolidinylcarbonyl)cyclopropyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 22)-   23.    1-{4-[2-oxo-2-(1-piperidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 23)-   24.    1-{4-[2-(3,3-difluoro-1-pyrrolidinyl)-2-oxoethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 24)-   25.    N-methyl-N-propyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 25)-   26.    N-cyclopentyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 26)-   27.    N-methyl-N-(2-thienylmethyl)-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide    (Example 27)-   28.    {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetonitrile    (Example 28)-   29.    {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanol    (Example 29)-   30.    N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide    (Example 30)-   31.    1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-pyrrolidinone    (Example 31)-   32.    N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)propanamide    (Example 32)-   33.    N-ethyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide    (Example 33)-   34.    1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-piperidinone    (Example 34)-   35.    1-methyl-5-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-2-pyrrolidinone    (Example 35)-   36.    N-[3-(1H-imidazol-1-yl)propyl]-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 36)-   37.    N-methyl-N-[2-(2-thienyl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 37)-   38.    N-methyl-N-[2-(1H-1,2,4-triazol-1-yl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 38)-   39.    N-methyl-N-(1,3-thiazol-2-ylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 39)-   40.    N-methyl-N-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 40)-   41.    N-methyl-N-(2-thienylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 41)-   42.    N-methyl-N-(3-pyridinylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 42)-   43.    N-(2-furanylmethyl)-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 43)-   44.    N-[(4-fluorophenyl)methyl]-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide    (Example 44)-   45.    1-[4-(4-morpholinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole    (Example 45)-   46.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)methanesulfonamide    (Example 46)-   47.    1-{4-[1-fluoro-2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   48.    1-{4-[1,1-difluoro-2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   49.    N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)methanesulfonamide-   50.    1-(4-{[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]methyl}phenyl)-2-pyrrolidinone-   51.    N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-1-pyrrolidinecarboxamide-   52.    5-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-2-pyrrolidinone-   53.    N-(1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}ethyl)acetamide-   54.    N-methyl-N-(1-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}ethyl)acetamide-   55.    1-[4-(1-acetyl-2-pyrrolidinyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   56.    1-(2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}ethyl)-2-pyrrolidinone-   57.    1-{4-[(1,1-dioxido-2-isothiazolidinyl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   58.    2-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)propanamide-   59.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)butanamide-   60.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-thiophenecarboxamide-   61.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)propanamide-   62.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide-   63.    N-methyl-2-phenyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide-   64.    N-(2-hydroxyethyl)-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   65.    N-methyl-N-[2-(methyloxy)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   66.    N-methyl-N-[2-(methylamino)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   67.    1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}carbonyl)-3-pyrrolidinol-   68.    N-methyl-1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}carbonyl)-3-pyrrolidinamine-   69.    1-[4-(1-azetidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   70.    1-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}carbonyl)-3-azetidinol-   71.    (3,3-difluorocyclobutyl){4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanone-   72.    1-[4-(1H-imidazol-1-yl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   73.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propenamide-   74.    N-(1-methylethenyl)-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propenamide-   75.    N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propenamide-   76.    1-{4-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   77.    1-{4-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   78.    N-ethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   79.    N-methyl-N-(1-methylethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   80.    1-[4-(1-piperidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   81.    N,N-diethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   82.    N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide-   83.    1-{4-[2-oxo-2-(2-phenyl-1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   84.    N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)benzamide-   85.    1-[4-(1,3-oxazol-5-yl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   86.    1-[4-(propyloxy)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   87.    1-[4-(1-methyl-1H-imidazol-4-yl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   88.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propanesulfonamide-   89.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)cyclopropanesulfonamide-   90.    N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)cyclopentanesulfonamide-   91.    1-[4-(1-pyrrolidinylsulfonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   92.    N-(2-methylpropyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide-   93.    1-[4-(4-morpholinylsulfonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   94.    N-[2-(methyloxy)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide-   95.    N-[2-(1-pyrrolidinyl)ethyl]-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide-   96.    N-(tetrahydro-2-furanylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide-   97.    1-[4-(1H-imidazol-1-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   98.    1-[4-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   99.    1-[4-(1H-pyrazol-1-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   100.    1-[4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   101.    1-[4-(2H-1,2,3-triazol-2-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   102.    1-{4-[(4-methyl-1H-pyrazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   103.    1-{4-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   104.    3-(trifluoromethyl)-1-(4-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)-4,5,6,7-tetrahydro-1H-indazole-   105.    3-(trifluoromethyl)-1-(4-{[5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)-4,5,6,7-tetrahydro-1H-indazole-   106.    1-(4-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   107.    1-(4-{[3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   108.    1-{4-[(2-methyl-1H-imidazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   109.    1-(4-{[2-(1-methylethyl)-1H-imidazol-1-yl]methyl}phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   110.    1-{4-[(4-phenyl-1H-imidazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   111.    1-{4-[(4-bromo-1H-pyrazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole-   112.    N-methyl-1H-imidazol-2-yl){4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanone-   113.    N-methyl-N-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-1-pyrrolidinecarboxamide    and salts and solvates thereof.

It will be appreciated that the invention includes the following furtheraspects. Hereinafter, the term “a compound of the invention” refers tocompounds of formula (II), their salts and their solvates as defined inany aspect of the invention (except Intermediate compounds in chemicalprocesses). The embodiments described in respect of the first aspectapply equally to each of these further aspects:

-   i) the use of a compound of formula (II) or a salt or solvate    thereof in the manufacture of a medicament for treating a disease or    condition mediated by a reduction or imbalance in glutamate receptor    function in a mammal;-   ii) a compound of formula (II) or a salt or solvate thereof for use    in treating a disease or condition mediated by a reduction or    imbalance in glutamate receptor function in a mammal;-   iii) a method of treatment of a disease or condition mediated by a    reduction or imbalance in glutamate receptor function in a mammal    comprising administering an effective amount of a compound of    formula (II) or a salt or solvate thereof;-   iv) a combination product of a compound of formula (II) or a salt or    solvate thereof with an antipsychotic;-   v) a pharmaceutical composition comprising a combination product as    defined in vi) above and at least one carrier, diluent or excipient;-   vi) the use of a combination product as defined in vi) above in the    manufacture of a medicament for treating a disease or condition    mediated by a reduction or imbalance in glutamate receptor function    in a mammal;-   vii) a combination product as defined in vi) above for use in    treating a disease or condition mediated by a reduction or imbalance    in glutamate receptor function in a mammal;-   viii) a combination product as defined in vi) above for use as a    medicament;-   ix) a method of treatment of a disease or condition mediated by a    reduction or imbalance in glutamate receptor function in a mammal    comprising administering an effective amount of a combination    product as defined in vi) above.

In the case of aspects ii), iii), iv), vii), viii), ix) and x), relevantdiseases or conditions are: psychosis and psychotic disorders (includingschizophrenia, schizo-affective disorder, schizophreniform diseases,brief reactive psychosis, child onset schizophrenia,“schizophrenia-spectrum” disorders such as schizoid or schizotypalpersonality disorders, acute psychosis, alcohol psychosis, drug-inducedpsychosis, autism, delerium, mania (including acute mania), manicdepressive psychosis, hallucination, endogenous psychosis, organicpsychosyndrome, paranoid and delusional disorders, puerperal psychosis,and psychosis associated with neurodegenerative diseases such asAlzheimer's disease); substance related disorders (includingalcohol-related disorders and nicotine-related disorders); cognitiveimpairment (e.g. the treatment of impairment of cognitive functionsincluding attention, orientation, memory (i.e. memory disorders,amnesia, amnesic disorders and age-associated memory impairment) andlanguage function, and including cognitive impairment as a result ofstroke, Alzheimer's disease, Aids-related dementia or other dementiastates, as well as other acute or sub-acute conditions that may causecognitive decline such as delirium or depression (pseudodementia states)trauma, aging, stroke, neurodegeneration, drug-induced states,neurotoxic agents), mild cognitive impairment, age related cognitiveimpairment, autism related cognitive impairment, Down's syndrome,cognitive deficit related to psychosis, post-electroconvulsive treatmentrelated cognitive disorders; anxiety disorders (including generalisedanxiety disorder, social anxiety disorder, agitation, tension, social oremotional withdrawal in psychotic patients, panic disorder, andobsessive compulsive disorder); neurodegenerative diseases (such asAlzheimer's disease, amyotrophic lateral sclerosis, motor neuronedisease and other motor disorders such as Parkinson's disease (includingrelief from locomotor deficits and/or motor disability, including slowlyincreasing disability in purposeful movement, tremors, bradykinesia,hyperkinesia (moderate and severe), akinesia, rigidity, disturbance ofbalance and co-ordination, and a disturbance of posture), dementia inParkinson's disease, dementia in Huntington's disease,neuroleptic-induced Parkinsonism and tardive dyskinesias,neurodegeneration following stroke, cardiac arrest, pulmonary bypass,traumatic brain injury, spinal cord injury or the like, anddemyelinating diseases such as multiple sclerosis and amyotrophiclateral sclerosis); depression (which term includes bipolar (manic)depression (including type I and type II), unipolar depression, singleor recurrent major depressive episodes with or without psychoticfeatures, catatonic features, melancholic features, atypical features(e.g. lethargy, over-eating/obesity, hypersomnia) or postpartum onset,seasonal affective disorder and dysthymia, depression-related anxiety,psychotic depression, and depressive disorders resulting from a generalmedical condition including, but not limited to, myocardial infarction,diabetes, miscarriage or abortion); post-traumatic stress syndrome;attention deficit disorder; attention deficit hyperactivity disorder;drug-induced (phencyclidine, ketamine and other dissociativeanaesthetics, amphetamine and other psychostimulants and cocaine)disorders; Huntingdon's chorea; tardive dyskinesia; dystonia; myoclonus;spasticity; obesity; stroke; sexual dysfunction; sleep disorders andsome forms of epilepsy.

Within the context of the present invention, the terms describing theindications used herein are classified in the Diagnostic and StatisticalManual of Mental Disorders, 4th Edition, published by the AmericanPsychiatric Association (DSM-IV) and/or the International Classificationof Diseases, 10th Edition (ICD-10). The various subtypes of thedisorders mentioned herein are contemplated as part of the presentinvention. Numbers in brackets after the listed diseases below refer tothe classification code in DSM-IV.

Within the context of the present invention, the term “psychoticdisorder” includes:—

Schizophrenia including the subtypes Paranoid Type (295.30),Disorganised Type (295.10), Catatonic Type (295.20), UndifferentiatedType (295.90) and Residual Type (295.60); Schizophreniform Disorder(295.40); Schizoaffective Disorder (295.70) including the subtypesBipolar Type and Depressive Type; Delusional Disorder (297.1) includingthe subtypes Erotomanic Type, Grandiose Type, Jealous Type, PersecutoryType, Somatic Type, Mixed Type and Unspecified Type; Brief PsychoticDisorder (298.8); Shared Psychotic Disorder (297.3); Psychotic DisorderDue to a General Medical Condition including the subtypes With Delusionsand With Hallucinations; Substance-Induced Psychotic Disorder includingthe subtypes With Delusions (293.81) and With Hallucinations (293.82);and Psychotic Disorder Not Otherwise Specified (298.9).

Compounds of the invention may also be of use in the treatment of thefollowing disorders:—

Depression and mood disorders including Major Depressive Episode, ManicEpisode, Mixed Episode and Hypomanic Episode; Depressive Disordersincluding Major Depressive Disorder, Dysthymic Disorder (300.4),Depressive Disorder Not Otherwise Specified (311); Bipolar Disordersincluding Bipolar I Disorder, Bipolar II Disorder (Recurrent MajorDepressive Episodes with Hypomanic Episodes) (296.89), CyclothymicDisorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80);Other Mood Disorders including Mood Disorder Due to a General MedicalCondition (293.83) which includes the subtypes With Depressive Features,With Major Depressive-like Episode, With Manic Features and With MixedFeatures), Substance-Induced Mood Disorder (including the subtypes WithDepressive Features, With Manic Features and With Mixed Features) andMood Disorder Not Otherwise Specified (296.90):

Anxiety disorders including Panic Attack; Panic Disorder including PanicDisorder without Agoraphobia (300.01) and Panic Disorder withAgoraphobia (300.21); Agoraphobia; Agoraphobia Without History of PanicDisorder (300.22), Specific Phobia (300.29, formerly Simple Phobia)including the subtypes Animal Type, Natural Environment Type,Blood-Injection-Injury Type, Situational Type and Other Type), SocialPhobia (Social Anxiety Disorder, 300.23), Obsessive-Compulsive Disorder(300.3), Posttraumatic Stress Disorder (309.81), Acute Stress Disorder(308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due toa General Medical Condition (293.84), Substance-Induced AnxietyDisorder, Separation Anxiety Disorder (309.21), Adjustment Disorderswith Anxiety (309.24) and Anxiety Disorder Not Otherwise Specified(300.00):

Substance-related disorders including Substance Use Disorders such asSubstance Dependence, Substance Craving and Substance Abuse;Substance-Induced Disorders such as Substance Intoxication, SubstanceWithdrawal, Substance-Induced Delirium, Substance-Induced PersistingDementia, Substance-Induced Persisting Amnestic Disorder,Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder,Substance-Induced Anxiety Disorder, Substance-Induced SexualDysfunction, Substance-Induced Sleep Disorder and HallucinogenPersisting Perception Disorder (Flashbacks); Alcohol-Related Disorderssuch as Alcohol Dependence (303.90), Alcohol Abuse (305.00), AlcoholIntoxication (303.00), Alcohol Withdrawal (291.81), Alcohol IntoxicationDelirium, Alcohol Withdrawal Delirium, Alcohol-Induced PersistingDementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-InducedPsychotic Disorder, Alcohol-Induced Mood Disorder, Alcohol-InducedAnxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-InducedSleep Disorder and Alcohol-Related Disorder Not Otherwise Specified(291.9); Amphetamine (or Amphetamine-Like)-Related Disorders such asAmphetamine Dependence (304.40), Amphetamine Abuse (305.70), AmphetamineIntoxication (292.89), Amphetamine Withdrawal (292.0), AmphetamineIntoxication Delirium, Amphetamine Induced Psychotic Disorder,Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced SleepDisorder and Amphetamine-Related Disorder Not Otherwise Specified(292.9); Caffeine Related Disorders such as Caffeine Intoxication(305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced SleepDisorder and Caffeine-Related Disorder Not Otherwise Specified (292.9);Cannabis-Related Disorders such as Cannabis Dependence (304.30),Cannabis Abuse (305.20), Cannabis Intoxication (292.89), CannabisIntoxication Delirium, Cannabis-Induced Psychotic Disorder,Cannabis-Induced Anxiety Disorder and Cannabis-Related Disorder NotOtherwise Specified (292.9); Cocaine-Related Disorders such as CocaineDependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication(292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium,Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder,Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction,Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder NotOtherwise Specified (292.9); Hallucinogen-Related Disorders such asHallucinogen Dependence (304.50), Hallucinogen Abuse (305.30),Hallucinogen Intoxication (292.89), Hallucinogen Persisting PerceptionDisorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium,Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced MoodDisorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-RelatedDisorder Not Otherwise Specified (292.9); Inhalant-Related Disorderssuch as Inhalant Dependence (304.60), Inhalant Abuse (305.90), InhalantIntoxication (292.89), Inhalant Intoxication Delirium, Inhalant-InducedPersisting Dementia, Inhalant-Induced Psychotic Disorder,Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder andInhalant-Related Disorder Not Otherwise Specified (292.9);Nicotine-Related Disorders such as Nicotine Dependence (305.1), NicotineWithdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified(292.9); Opioid-Related Disorders such as Opioid Dependence (304.00),Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal(292.0), Opioid Intoxication Delirium, Opioid-Induced PsychoticDisorder, Opioid-Induced Mood Disorder, Opioid-Induced SexualDysfunction, Opioid-Induced Sleep Disorder and Opioid-Related DisorderNot Otherwise Specified (292.9); Phencyclidine (orPhencyclidine-Like)-Related Disorders such as Phencyclidine Dependence(304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication(292.89), Phencyclidine Intoxication Delirium, Phencyclidine-InducedPsychotic Disorder, Phencyclidine-Induced Mood Disorder,Phencyclidine-Induced Anxiety Disorder and Phencyclidine-RelatedDisorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, orAnxiolytic-Related Disorders such as Sedative, Hypnotic, or AnxiolyticDependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40),Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative,Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, orAnxiolytic Intoxication Delirium, Sedative, Hypnotic, or AnxiolyticWithdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-PersistingDementia, Sedative-, Hypnotic-, or Anxiolytic-Persisting AmnesticDisorder, Sedative-, Hypnotic-, or Anxiolytic-Induced PsychoticDisorder, Sedative-, Hypnotic-, or Anxiolytic-Induced Mood Disorder,Sedative-, Hypnotic-, or Anxiolytic-Induced Anxiety Disorder Sedative-,Hypnotic-, or Anxiolytic-Induced Sexual Dysfunction, Sedative-,Hypnotic-, or Anxiolytic-Induced Sleep Disorder and Sedative-,Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified(292.9); Polysubstance-Related Disorder such as Polysubstance Dependence(304.80); and Other (or Unknown) Substance-Related Disorders such asAnabolic Steroids, Nitrate Inhalants and Nitrous Oxide:

Sleep disorders including primary sleep disorders such as Dyssomniassuch as Primary Insomnia (307.42), Primary Hypersomnia (307.44),Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), CircadianRhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified(307.47); primary sleep disorders such as Parasomnias such as NightmareDisorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder(307.46) and Parasomnia Not Otherwise Specified (307.47); SleepDisorders Related to Another Mental Disorder such as Insomnia Related toAnother Mental Disorder (307.42) and Hypersomnia Related to AnotherMental Disorder (307.44); Sleep Disorder Due to a General MedicalCondition, in particular sleep disturbances associated with suchdiseases as neurological disorders, neuropathic pain, restless legsyndrome, heart and lung diseases; and Substance-Induced Sleep Disorderincluding the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Typeand Mixed Type; sleep apnea and jet-lag syndrome:

Autism Spectrum Disorders including Autistic Disorder (299.00),Asperger's Disorder (299.80), Rett's Disorder (299.80), ChildhoodDisintegrative Disorder (299.10) and Pervasive Disorder Not OtherwiseSpecified (299.80, including Atypical Autism).

Attention-Deficit/Hyperactivity Disorder including the subtypesAttention-Deficit/Hyperactivity Disorder Combined Type (314.01),Attention-Deficit/Hyperactivity Disorder Predominantly Inattentive Type(314.00), Attention-Deficit/Hyperactivity Disorder Hyperactive-ImpulseType (314.01) and Attention-Deficit/Hyperactivity Disorder Not OtherwiseSpecified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorderssuch as Conduct Disorder including the subtypes childhood-onset type(321.81), Adolescent-Onset Type (312.82) and Unspecified Onset (312.89),Oppositional Defiant Disorder (313.81) and Disruptive Behaviour DisorderNot Otherwise Specified; and Tic Disorders such as Tourette's Disorder(307.23):

Personality Disorders including the subtypes Paranoid PersonalityDisorder (301.0), Schizoid Personality Disorder (301.20), SchizotypalPersonality Disorder (301,22), Antisocial Personality Disorder (301.7),Borderline Personality Disorder (301,83), Histrionic PersonalityDisorder (301.50), Narcissistic Personality Disorder (301,81), AvoidantPersonality Disorder (301.82), Dependent Personality Disorder (301.6),Obsessive-Compulsive Personality Disorder (301.4) and PersonalityDisorder Not Otherwise Specified (301.9):

Enhancement of cognition including the treatment of cognition impairmentin other diseases such as schizophrenia, bipolar disorder, depression,other psychiatric disorders and psychotic conditions associated withcognitive impairment, e.g. Alzheimer's disease: and

Sexual dysfunctions including Sexual Desire Disorders such as HypoactiveSexual Desire Disorder (302.71), and Sexual Aversion Disorder (302.79);sexual arousal disorders such as Female Sexual Arousal Disorder (302.72)and Male Erectile Disorder (302.72); orgasmic disorders such as FemaleOrgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) andPremature Ejaculation (302.75); sexual pain disorder such as Dyspareunia(302.76) and Vaginismus (306.51); Sexual Dysfunction Not OtherwiseSpecified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism(302.81), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism(302.83), Sexual Sadism (302.84), Transvestic Fetishism (302.3),Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9);gender identity disorders such as Gender Identity Disorder in Children(302.6) and Gender Identity Disorder in Adolescents or Adults (302.85);and Sexual Disorder Not Otherwise Specified (302.9).

All of the various forms and sub-forms of the disorders mentioned hereinare contemplated as part of the present invention.

Within the context of the present invention, the term “cognitiveimpairment” includes for example the treatment of impairment ofcognitive functions including attention, orientation, learningdisorders, memory (i.e. memory disorders, amnesia, amnesic disorders,transient global amnesia syndrome and age-associated memory impairment)and language function; cognitive impairment as a result of stroke,Alzheimer's disease, Huntington's disease, Pick disease, Aids-relateddementia or other dementia states such as Multiinfarct dementia,alcoholic dementia, hypotiroidism-related dementia, and dementiaassociated to other degenerative disorders such as cerebellar atrophyand amyotropic lateral sclerosis; other acute or sub-acute conditionsthat may cause cognitive decline such as delirium or depression(pseudodementia states) trauma, head trauma, age related cognitivedecline, stroke, neurodegeneration, drug-induced states, neurotoxicagents, mild cognitive impairment, age related cognitive impairment,autism related cognitive impairment, Down's syndrome, cognitive deficitrelated to psychosis, and post-electroconvulsive treatment relatedcognitive disorders; and dyskinetic disorders such as Parkinson'sdisease, neuroleptic-induced parkinsonism, and tardive dyskinesias.

In one embodiment, the present invention provides a compound of theinvention for use in treating schizophrenia or impairment of cognition.

In one embodiment, the present invention provides a use of a compound ofthe invention in the manufacture of a medicament for treatingschizophrenia or impairment of cognition.

In one embodiment, the present invention provides a method of treatmentof schizophrenia or impairment of cognition.

It is to be understood that the term “a disease or condition mediated bya reduction or imbalance in glutamate receptor function in a mammal”encompasses “a disease or condition caused by a reduction or imbalancein glutamate receptor function in a mammal”.

The compounds of the invention may be used in combination with one ormore of the following agents to treat psychotic disorders: i)antipsychotics (such as olanzapine, risperidone, clozapine, ziprazidone,talnetant); ii) drugs for extrapyramidal side effects, for exampleanticholinergics (such as benztropine, biperiden, procyclidine,trihexyphenidyl), antihistamines (such as diphenhydramine),dopaminergics (such as amantadine); iii) antidepressants; iv)anxiolytics; v) cognitive enhancers for example cholinesteraseinhibitors (such as tacrine, donepezil, rivastigmine, galantamine).

The compounds of the invention may be used in combination withantidepressants to treat depression and mood disorders.

The compounds of the invention may be used in combination with one ormore of the following agents to treat bipolar disease: i) moodstabilisers; ii) antipsychotics; iii) antidepressants.

The compounds of the invention may be used in combination with one ormore of the following agents to treat anxiety disorders: i) anxiolytics;ii) antidepressants.

The compounds of the invention may be used in combination with one ormore of the following agents to improve nicotine withdrawal and reducenicotine craving: i) nicotine replacement therapy, for example asublingual formulation of nicotine beta-cyclodextrin and nicotinepatches; ii) drugs for treating nicotine addition, for examplebupropion.

The compounds of the invention may be used in combination with one ormore of the following agents to improve alcohol withdrawal and reducealcohol craving: i) NMDA receptor antagonists for example acamprosate;ii) GABA receptor agonists for example tetrabamate; iii) Opioid receptorantagonists for example naltrexone.

The compounds of the invention may be used in combination with one ormore of the following agents to improve opiate withdrawal and reduceopiate craving: i) opioid mu receptor agonist/opioid kappa receptorantagonist for example buprenorphine; ii) opioid receptor antagonistsfor example naltrexone; iii) vasodilatory antihypertensives for examplelofexidine.

The compounds of the invention may be used in combination with one ormore of the following agents to treat sleeping disorders: i)benzodiazepines for example temazepam, lormetazepam, estazolam,triazolam; ii) non-benzodiazepine hypnotics for example zolpidem,zopiclone, zaleplon, indiplon; iii) barbiturates for exampleaprobarbital, butabarbital, pentobarbital, secobarbita, phenobarbital;iv) antidepressants; v) other sedative-hypnotics for example chloralhydrate, chlormethiazole.

The compounds of the invention may be used in combination with one ormore of the following agents to treat anorexia: i) appetite stimulantsfor example cyproheptidine; ii) antidepressants; iii) antipsychotics;iv) zinc; v) premenstrual agents for example pyridoxine andprogesterones.

The compounds of the invention may be used in combination with one ormore of the following agents to treat bulimia: i) antidepressants; ii)opioid receptor antagonists; iii) antiemetics for example ondansetron;iv) testosterone receptor antagonists for example flutamide; v) moodstabilisers; vi) zinc; vii) premenstrual agents.

The compounds of the invention may be used in combination with one ormore of the following agents to treat autism: i) antipsychotics; ii)antidepressants; iii) anxiolytics; iv) stimulants for examplemethylphenidate, amphetamine formulations, pemoline.

The compounds of the invention may be used in combination with one ormore of the following agents to treat Attention Deficit HyperactivityDisorder: i) stimulants for example methylphenidate, amphetamineformulations, pemoline; ii) non-stimulants for example norepinephrinereuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists(such as clonidine), antidepressants, modafinil, cholinesteraseinhibitors (such as galantamine and donezepil).

The compounds of the invention may be used in combination with one ormore of the following agents to treat personality disorders: i)antipsychotics; ii) antidepressants; iii) mood stabilisers; iv)anxiolytics.

The compounds of the invention may be used in combination with one ormore of the following agents to treat male sexual dysfunction: i)phosphodiesterase V inhibitors, for example vardenafil, sildenafil; ii)dopamine agonists/dopamine transport inhibitors for example apomorphine,buproprion; iii) alpha adrenoceptor antagonists for examplephentolamine; iv) prostaglandin agonists for example alprostadil; v)testosterone agonists such as testosterone; vi) serotonin transportinhibitors for example serotonin reuptake inhibitors; v) noradrenalinetransport inhibitors for example reboxetine; vii) 5-HT1A agonists, forexample flibanserine.

The compounds of the invention may be used in combination with one ormore of the following agents to treat female sexual dysfunction: i) thesame agents specified for male sexual dysfunction, ii) an estrogenagonist such as estradiol.

Antipsychotic drugs include Typical Antipsychotics (for examplechlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine,prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindoneand loxapine); and Atypical Antipsychotics (for example clozapine,olanzapine, risperidone, quetiapine, aripirazole, ziprasidone,amisulpride, ziprazidone and talnetant).

Antidepressant drugs include serotonin reuptake inhibitors (such ascitalopram, escitalopram, fluoxetine, paroxetine and sertraline); dualserotonin/noradrenaline reuptake inhibitors (such as venlafaxine,duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such asreboxetine); tricyclic antidepressants (such as amitriptyline,clomipramine, imipramine, maprotiline, nortriptyline and trimipramine);monoamine oxidase inhibitors (such as isocarboxazide, moclobemide,phenelzine and tranylcypromine); and others (such as bupropion,mianserin, mirtazapine, nefazodone and trazodone).

Mood stabiliser drugs include lithium, sodium valproate/valproicacid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate andtiagabine.

Anxiolytics include benzodiazepines such as alprazolam and lorazepam.

The compounds of the invention may be administered in conventionaldosage forms prepared by combining a compound of the invention withstandard pharmaceutical carriers or diluents according to conventionalprocedures well known in the art. These procedures may involve mixing,granulating and compressing or dissolving the ingredients as appropriateto the desired preparation.

The pharmaceutical compositions of the invention may be formulated foradministration to mammals including humans. The compositions may beformulated for administration by any route. The compositions may beformulated for oral, topical, or parenteral administration, and may bein the form of tablets, capsules, powders, granules, lozenges, creams orliquid preparations, such as oral or sterile parenteral solutions orsuspensions.

The topical formulations of the present invention may be presented as,for instance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, suchas cream or ointment bases and ethanol or oleyl alcohol for lotions.Such carriers may be present as from about 1% up to about 98% of theformulation. More usually they will form up to about 80% of theformulation.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrrolidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerine, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g.cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are preparedutilising the compound and a sterile vehicle, for example water. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilisedbefore filling into a suitable vial or ampoule and sealing.

Agents such as a local anaesthetic, preservative and buffering agentscan be dissolved in the vehicle. To enhance the stability, thecomposition can be frozen after filling into the vial and the waterremoved under vacuum. The dry lyophilised powder is then sealed in thevial and an accompanying vial of water for injection may be supplied toreconstitute the liquid prior to use. Parenteral suspensions areprepared in substantially the same manner except that the compound issuspended in the vehicle instead of being dissolved and sterilisationcannot be accomplished by filtration. The compound can be sterilised byexposure to ethylene oxide before suspending in the sterile vehicle. Asurfactant or wetting agent may be included in the composition tofacilitate uniform distribution of the compound.

The compositions may contain from 0.1% by weight, for example from10-60% by weight, of the active material, depending on the method ofadministration. Where the compositions comprise dosage units, each unitmay, for example contain from 0.1 to 20 mg of the active ingredient. Forexample, such a unit may contain from 1 to 10 mg. The dosage as employedfor adult human treatment may, for example, range from 2 to 50 mg perday, for instance 5 to 20 mg per day depending on the route andfrequency of administration (though in some instances, a dosage of 50 mgto 100 mg per day may be appropriate). Based on a 75 kg individual, sucha dosage corresponds to 0.027 to 0.667 mg/kg per day. Suitably thedosage is from 0.05 to 0.3 mg/kg per day.

It will be recognised by one of skill in the art that the optimalquantity and spacing of individual dosages of a compound of theinvention will be determined by the nature and extent of the conditionbeing treated, the form, route and site of administration, and theparticular mammal being treated, and that such optimums can bedetermined by conventional techniques. It will also be appreciated byone of skill in the art that the optimal course of treatment, i.e. thenumber of doses of a compound of the invention given per day for adefined number of days, can be ascertained by those skilled in the artusing conventional course of treatment determination tests.

It is to be understood that “treatment” as used herein includesprophylaxis as well as alleviation of established symptoms. In oneembodiment, the mammal to be treated is a human.

The invention is illustrated by the Examples described below.

Starting materials were obtained from commercial suppliers and usedwithout further purification unless otherwise stated. Flashchromatography was carried out using pre-packed Isolute Flash™ orBiotage™ silica-gel columns as the stationary phase and analytical gradesolvents as the eluent.

NMR spectra were obtained at 298K, at the frequency stated using eithera Bruker™ DPX400 or an Oxford Instruments™ 250 MHz machine and run as adilute solution of CDCl₃ unless otherwise stated. All NMR spectra werereference to tetramethylsilane (TMS δ_(H) 0, δ_(C) 0). All couplingconstants are reported in hertz (Hz), and multiplicities are labelled s(singlet), bs, (broad singlet), d (doublet), t (triplet), q (quartet),dd (doublet of doublets), dt (doublet of triplets) and m (multiplet).

Total ion current traces were obtained for electrospray positive andnegative ionisation (ES+/ES−) and atmospheric pressure chemical positiveand negative ionisation (AP+/AP−).

All quoted retention times are as measured using LC/MS (LiquidChromatography/Mass Spectrometry). Where appropriate, these retentiontimes were used as a guide for purification using mass-directedauto-preparation (MDAP), which refers to purification by HPLC, whereinfraction collection is triggered by detection of the programmed mass ionfor the compound of interest.

Unless otherwise stated, all compounds with chiral centre(s) areracemic.

LC/MS Conditions for Examples 1-35 and 45-113 Column: Waters Atlantis,4.6 mm × 50 mm. The stationary phase particle size is 3 um. Solvents: A:Aqueous solvent = Water + 0.05% Formic Acid; B: Organic solvent =Acetonitrile + 0.05% Formic Acid Methods: The generic method used has a5 minute runtime. Time/min % B 0   3 0.1 3 4   97 4.8 97 4.9 3 5.0 3Flow rate: 3 ml/min Injection volume: 5 ul Column 30 deg C. temperature:UV wavelength 220-330 nm range:

LC/MS Conditions for Examples 36-44 Column: Waters Atlantis, 4.6 mm × 20mm. The stationary phase particle size is 3 um. Solvents: A: Aqueoussolvent = Water + 0.1% Formic Acid; B: Organic solvent = Acetonitrile +0.1% Formic Acid Methods: The generic method has a 5.5 minute runtimeusing the following gradient programme. Time/min % B 0   3 0.7 3 4.5 1005.3 100 5.4 3 5.5 3 Flow rate: 1 ml/mins Iniection volume: 2 ul fullloop injection Column temperature: ambient UV wavelength range: 210-350nmMDAP Conditions for Examples 1-35 and 45-113

-   -   Column: Waters Atlantis, 19 mm×100 mm (small scale) and 30        mm×100 mm (large scale). Stationary phase particle size=5 um.    -   Solvents: A: Aqueous solvent=Water+0.1% Formic Acid; B: Organic        solvent=Acetonitrile+0.1% Formic Acid. Make up        solvent=Methanol:Water 80:20. Needle rinse solvent=Methanol    -   Methods: There are five methods used depending on the analytical        retention time of the compound of interest. They have a        13.5-minute runtime, which comprises of a 10-minute gradient        followed by a 3.5 minute column flush and re-equilibration step.        -   Large/Small Scale 1.0-1.5=5-30% B        -   Large/Small Scale 1.5-2.2=15-55% B        -   Large/Small Scale 2.2-2.9=30-85% B        -   Large/Small Scale 2.9-3.6=50-99% B        -   Large/Small Scale 3.6-5.0=80-99% B (in 6 minutes followed by            7.5 minutes flush and re-equilibration)    -   Flow rate: 20 mls/min (Small Scale) or 40 mls/min (Large Scale).        MDAP Conditions for Example 36-44    -   Column: Waters Atlantis, 19 mm×100 mm with particle size 5 mm.    -   Solvents: A: Aqueous solvent=Water+0.1% Trifluoroacetic Acid; B:        Organic solvent=Acetonitrile+0.1% Trifluoroacetic Acid; Make up        solvent=Methanol:Water 80:20+0.1% Formic Acid; Needle rinse        solvent=Methanol    -   Methods: There are five methods used depending on the analytical        retention time of the compound of interest. They have a 20        minute runtime, which comprises of a 15.5 minute gradient        followed by a 3.5 minute column flush and re-equilibration step.        -   Method 1.8-2.1=0-30% B        -   Method 2.1-2.6=10-45% B        -   Method 2.6-3.1=15-65% B        -   Method 3.1-4.1=30-75% B        -   Method >4.1=50-100% B (in 14 minutes followed by 5 minutes            flush and re-equilibration)    -   Flow rate: 20 mls/min    -   Injection volume: 500 ul partial loop injection.    -   Column temperature: ambient

Abbreviations DCM Dichloromethane TEA Triethylamine TMS-Cl-Trimethylsilyl chloride DME Dimethyl ether ss saturated solution TFATrifluoroacetic acid DAD Diode Array Detector CD Circular dichroism a/a% percentage by area unde the curve LC/Mass Spec LiquidChromatography/Mass Spectrometry NMR Nuclear Magnetic Resonance SCXChromatography column supplied by Varian ™ THF Tetrahydrofuran DMSODimethylsulfoxide DMF Dimethylformamide DCM/MDCDichloromethane/Methylene dichloride CDI 1,1′-Carbonyldiimidazole LDALithium diisopropylamide EDC 1-ethyl-3-(dimethylaminopropyl)carbodiimideMsCl Methanesulfonyl chloride AcOH Acetic acid HOAt1-hydroxy-7-azabenzotriazole HOBt 1-hydroxybenzotriazole Pd on CPalladium on Charcoal MeCN Acetonitrile

In the procedures that follow, reference to an Intermediate or Exampleby number is typically provided. This is provided merely for assistanceto the skilled chemist to identify the starting material used. Thestarting material may not necessarily have been prepared from the batchreferred to. All reactions were either carried out under argon or may becarried out under argon.

Intermediates

Description 1 4-iodo-N,N-dimethylbenzamide

A suspension of dimethylamine hydrochloride (2.45 g, 30 mmol) indichloromethane (150 ml) was cooled in an ice/methanol bath and thentreated with triethylamine (6.0 g, 59 mmol) followed by 4-iodobenzoylchloride (8.0 g, 30 mmol) portionwise with stirring under an atmosphereof argon. The reaction mixture was allowed to stir at room temperaturefor 30 minutes before the solution was washed with water (2×100 ml). Theorganic layer was separated, dried over sodium sulphate, and evaporatedunder reduced pressure to give the title compound as a light beigecoloured solid (7.73 g, 94%).

LC/mass spec (ES): Found 276 (ES+), retention time 2.30 mins. C₉H₁₀INOrequires 275.

¹H-NMR (400 MHz, CDCl₃): 2.97 (3H, s), 3.11 (3H, m), 7.16 (2H, m), 7.75(2H, m).

Description 2 4-iodo-N,N-dimethylbenzenesulfonamide

The title compound was prepared from pipsyl chloride and dimethylaminehydrochloride using a similar procedure to that used for Description 1.

LC/mass spec (ES): Found 312 (ES+), retention time 2.86 mins. C₈H₁₀INO₂Srequires 311.

¹H-NMR (400 MHz, CDCl₃): 2.70 (6H, m), 7.49 (2H, d, J=8 Hz), 7.91 (2H,d, J=8 Hz).

Description 3 2-(4-bromophenyl)-N,N-dimethylacetamide

A solution of 4-bromophenylacetic acid (960 mg, 4.49 mmol) indichloromethane (30 ml) was treated in one portion with solid1,1′-carbonyldiimidazole (730 mg, 4.5 mmol) at 20° C. with stirringunder argon. This mixture was allowed to stir at room temperature for 15minutes. Triethylamine (0.63 ml) was then added followed bydimethylamine hydrochloride (367 mg, 4.5 mmol) and the stirringcontinued for 1 hour. Most of the solvent was removed under reducedpressure and the residue added to a 20 g isolute silica sep-pak columnand eluted from 0-50% ethyl acetate in petroleum ether to give the titlecompound as a colourless solid (689 mg, 64%).

LC/mass spec (ES): Found 242 (ES+), retention time 2.36 mins. C₁₀H₁₂⁷⁹BrNO requires 241.

¹H-NMR (400 MHz, CDCl₃): 2.97 (3H, s), 3.00 (3H, s), 3.66 (2H, s), 7.12(2H, m), 7.44 (2H, m).

Description 4 Methyl4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoate

A mixture of methyl 4-iodobenzoate (1.40 g, 5.34 mmol),3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (1.22 g, 6.42 mmol),copper (I) iodide (1 mol %, 10 mg, 0.05 mmol),trans-1,2-diaminocyclohexane (10 mol %, 62 mg, 0.54 mmol) and potassiumcarbonate (1.56 g, 11.3 mmol) in 1,4-dioxane (8 ml) was stirred at 180°C. in a microwave reactor for 45 minutes, then fresh copper (I) iodide(1 mol %, 10 mg, 0.05 mmol) and trans-1,2-diaminocyclohexane (10 mol %,62 mg, 0.54 mmol) were added and the reaction stirred at 180° C. in amicrowave reactor for 1 h 45 minutes. The reaction mix was cooled andadded to a 50 g pre-packed silica column which was then eluted from0-50% ethyl acetate in petroleum ether to give a crop of the titlecompound as a brown oil (630 mg, 36%).

LC/mass spec (ES): Found 325 (ES+), retention time 3.78 mins.C₁₆H₁₅F₃N₂O₂ requires 324.

¹H-NMR (400 MHz, CDCl₃): 1.83 (4H, m), 2.68 (4H, m), 3.95 (3H, s), 7.61(2H, m), 8.15 (2H, m).

Description 54-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid

A mixture of methyl4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoate (600mg, 1.85 mmol), sodium hydroxide (81 mg, 2.0 mmol), in ethanol (4 ml)and water (4 ml) was stirred at reflux for 1 hour. The reaction mix wasallowed to cool and the ethanol was removed under reduced pressure andthe residue was partitioned between diethyl ether (10 ml) and water (10ml). The aqueous layer was separated and made acidic with 2N HCl, thenextracted with dichloromethane. The organic layer was dried over sodiumsulphate and evaporated under reduced pressure to give the titlecompound as a beige solid (222 mg, 39%)

LC/mass spec (ES): Found 311 (ES+), retention time 3.24 mins.C₁₅H₁₃F₃N₂O₂ requires 310.

¹H-NMR (400 MHz, CDCl₃): 1.85 (4H, m), 2.68 (2H, m), 2.79 (2H, m), 7.67(2H, m), 8.21 (2H, m).

Description 5a4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid

A mixture of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (950 mg,5.0 mmol), 4-iodobenzoic acid (1.24 g, 5.0 mmol), N,N-dimethylglycine(20 mol %, 103 mg, 1.0 mmol), copper (I) iodide (10 mol %, 95 mg, 0.5mmol) and potassium carbonate (1.45 g, 10.5 mmol) in dimethylsulfoxide(15 ml) was stirred at 130° C. in an oil bath under argon for 3.25hours. The reaction mix was then filtered under vacuum and the filtrateseparated between ethyl acetate and water. The aqueous layer wasretained and acidified to approximately Ph2 using 5M aqueous HCl. Theaqueous fraction was then washed 3 times with ethyl acetate. The organiclayers were combined and dried over sodium sulphate, and the solvent wasremoved by rotary evaporation to give the title compound as a brownsolid (1.62 g, 100%).

¹H-NMR (400 MHz, MeOD): 1.86 (4H, m), 2.66 (2H, m), 2.81 (2H, m), 7.68(2H, d, J=9 Hz), 8.18 (2H, d, J=9 Hz).

Description 6 Ethyl{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetate

A mixture of ethyl-4-bromophenylacetate (875 mg, 3.60 mmol),3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (570 mg, 3.00 mmol),potassium carbonate (842 mg, 6.10 mmol), copper (I) iodide (5 mol %, 29mg, 0.15 mmol), and (1R,2R)-N,N′-dimethyl-1,2-cyclohexanediamine (20 mol%, 85 mg, 0.60 mmol) in toluene (2 ml) was stirred under an atmosphereof argon at 130° C. in a microwave reactor for 1 h. Further copper (I)iodide (10 mg, 0.05 mmol), and(1R,2R)-N,N′-dimethyl-1,2-cyclohexanediamine (30 mg, 0.21 mmol) wasadded and heating continued at 130° C. for a total of 4 h. The reactionmix was cooled and added to a 20 g pre-packed silica column and elutedwith 0-20% ethyl acetate in petroleum ether to give the title compoundas a brown oil (0.92 g, 87%).

LC/mass spec (ES): Found 353 (ES+), retention time 3.70 mins.C₁₈H₁₉F₃N₂O₂ requires 352.

¹H-NMR (400 MHz, CDCl₃): 1.26 (3H, m), 1.81 (4H, m), 2.69 (4H, m), 3.66(2H, s), 4.15 (2H, m), 7.38 (2H, m), 7.45 (2H, m).

Description 7{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}aceticacid

A mixture of ethyl{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetate(0.92 g, 2.61 mmol), sodium hydroxide (114 mg, 2.85 mmol), in ethanol(10 ml) and water (10 ml) was stirred at reflux for 1 hour. The reactionmix was allowed to cool and the ethanol was removed under reducedpressure and the residue was made acidic with 5N HCl, then extractedinto dichloromethane. The organic layer was added to a 5 g pre-packedcolumn and eluted from 0-100% ethyl acetate in petroleum ether to givethe title compound as a pale yellow solid (0.42 g, 50%).

LC/mass spec (ES): Found 325 (ES+), retention time 3.00 mins.C₁₆H₁₅F₃N₂O₂ requires 324.

¹H-NMR (400 MHz, DMSO D6): 1.75 (4H, m), 2.60 (2H, m), 2.73 (2H, m),3.67 (2H, s) 7.43 (2H, d, J=8 Hz), 7.51 (2H, m), 12.43 (1H, bs).

Description 8 1-{[4-(bromomethyl)phenyl]carbonyl}pyrrolidine

A solution of 4-(bromomethyl)benzoic acid (2.43 g, 11.3 mmol) indichloromethane (40 ml) was treated in one portion with solid1,1′-carbonyldiimidazole (1.83 g, 11.3 mmol). This mixture was allowedto stir at room temperature for 15 minutes. Pyrrolidine (0.8 g, 11.3mmol) was then added and the stirring continued for 1 hour at roomtemperature. The reaction mixture was partitioned betweendichloromethane and saturated sodium bicarbonate solution. The organiclayer was dried over sodium sulphate and evaporated in vaccuo (i.e underreduced pressure) to give a yellow oil which was added to a 20 gpre-packed silica column and eluted from 20-50% ethyl acetate inpetroleum ether to give the title compound as a colourless solid (0.5 g,17%).

LC/mass spec (ES): Found 268 (ES+), retention time 2.46 mins. C₁₂H₁₄⁷⁹BrNO requires 267.

¹H-NMR (400 MHz, CDCl₃): 1.88 (2H, m), 1.97 (2H, m), 3.43 (2H, t, J=7Hz), 3.65 (2H, t, J=7 Hz), 4.50 (2H, s), 7.42 (2H, dd, J=7 Hz & 2 Hz),7.50 (2H, dd, J=7 Hz & 2 Hz).

Description 9 1-[2-(4-bromophenyl)propanoyl]pyrrolidine

A solution of 2-(4-bromophenyl)propanoic acid (215 mg, 0.94 mmol) indichloromethane (4 ml) was treated in one portion with solid1,1′-carbonyldiimidazole (152 g, 0.94 mmol). This mixture was allowed tostir at room temperature for 15 minutes. Pyrrolidine (67 mg, 0.94 mmol)was then added and the stirring continued for 1 hour at roomtemperature. Most of the solvent was removed under reduced pressure andthe residue added to a 5 g pre-packed silica column and eluted from0-50% ethyl acetate in petroleum ether to give the title compound as acolourless solid (189 mg, 71%).

LC/mass spec (ES): Found 282 (ES+), retention time 2.78 mins. C₁₃H₁₆⁷⁹BrNO requires 281.

¹H-NMR (400 MHz, CDCl₃): 1.43 (3H, d, J=7 Hz), 1.75-1.93 (4H, m), 3.16(1H, m), 3.37-3.56 (3H, m), 3.70 (1H, m), 7.19 (2H, m), 7.43 (2H, m).

Description 10

1-[(1-phenylcyclopropyl)carbonyl]pyrrolidine

The title compound was prepared from 1-phenylcyclopropanecarboxylic acidand pyrrolidine using a similar procedure to that described forDescription 8.

LC/mass spec (ES): Found 216 (ES+), retention time 2.45 mins. C₁₄H₁₇NOrequires 215.

¹H-NMR (400 MHz, CDCl₃): 1.14 (2H, m), 1.44 (2H, m), 1.72-1.81 (4H, m),3.17 (2H, m), 3.49 (2H, m), 7.19 (3H, m), 7.29 (2H, m).

Description 11 1-{[1-(4-iodophenyl)cyclopropyl]carbonyl}pyrrolidine

1-[(1-phenylcyclopropyl)carbonyl]pyrrolidine (0.75 g, 3.49 mmol) wasdissolved in glacial acetic acid (14 ml) and treated successively withconcentrated sulfuric acid (0.4 ml), water (1.5 ml), periodic acid (184mg, 0.8 mmol), and iodine (379 mg, 1.49 mmol). This mixture was thenstirred at 60° C. for 6 hours and then allowed to cool to roomtemperature. The reaction mixture was poured into a 10% aqueous solutionof sodium metabisulfite and extracted into ethyl acetate. The organiclayer was separated and dried over anhydrous sodium sulphate andevaporated under reduced pressure to give a yellow oil (1.45 g) whichwas added to a 20 g pre-packed silica column and eluted from 0-50% ethylacetate in petroleum ether to give the title compound as a yellow oil(0.62 g, 52%).

LC/mass spec (ES): Found 342 (ES+), retention time 2.94 mins. C₁₄H₁₆INOrequires 341.

¹H-NMR (400 MHz, CDCl₃): 1.13 (2H, m), 1.43 (2H, m), 1.72-1.82 (4H, m),3.17 (2H, m), 3.49 (2H, m), 6.95 (2H, m), 7.61 (2H, m).

Description 12 3-(4-bromophenyl)-N,N-dimethylpropanamide

A solution of 3-(4-bromophenyl)propionic acid (1.0 g, 4.37 mmol) indichloromethane (30 ml) was treated in one portion with solid1,1′-carbonyldiimidazole (707 mg, 4.36 mmol). This mixture was allowedto stir at room temperature for 15 minutes. Dimethylamine hydrochloride(360 mg, 4.42 mmol) was then added followed by diisopropylethylamine(0.76 ml, 4.4 mmol) and the stirring continued for 1 hour at roomtemperature. The reaction mixture was partitioned betweendichloromethane and saturated sodium bicarbonate solution. The organiclayer was dried over sodium sulphate and evaporated under reducedpressure to give the title compound as a colourless oil (972 mg, 87%).

LC/mass spec (ES): Found 256 (ES+), retention time 2.61 mins. C₁₁H₁₄⁷⁹BrNO requires 255.

¹H-NMR (400 MHz, CDCl₃): 2.59 (2H, t, J=8 Hz), 2.93 (8H, m), 7.11 (2H,m), 7.40 (2H, m).

Description 13 1-[3-(4-bromophenyl)propanoyl]pyrrolidine

The title compound was prepared from 3-(4-bromophenyl)propanoic acid andpyrrolidine using a similar procedure to that described for Description8, but without chromatographic purification.

LC/mass spec (ES): Found 282 (ES+), retention time 2.76 mins. C₁₃H₁₆⁷⁹BrNO requires 281. ¹H-NMR (400 MHz, CDCl₃): 1.79-1.94 (4H, m), 2.53(2H, t, J=8 Hz), 2.94 (2H, t, J=8 Hz), 3.30 (2H, t, J=7 Hz), 3.46 (2H,t, J=7 Hz), 7.11 (2H, m), 7.40 (2H, m).

Description 14 N-[(4-bromophenyl)methyl]-N-methylacetamide

A solution of triethylamine (0.22 ml, 1.6 mmol) in dichloromethane (10ml) was treated with acetyl chloride (0.08 ml, 1.10 mmol), followed by4-bromo-N-methylbenzylamine (210 mg, 1.05 mmol). This mixture was thenstirred under an atmosphere of argon for 10 minutes. The reactionmixture was washed twice with water and the organic layer was separatedand dried over sodium sulphate, and the solvent removed via rotaryevaporation to give a yellow oil which was purified on a 5 g sep-pakcolumn eluting from 0-100% ethyl acetate in petroleum ether to give thetitle compound as a yellow oil.

LC/mass spec (ES): Found 242 (ES+), retention time 2.39 mins. C₁₀H₁₂⁷⁹BrNO requires 241.

¹H-NMR (400 MHz, CDCl₃): 2.14 (3H, m), 2.90 (3H, m), 4.54 (2H, m), 7.13(2H, m), 7.47 (2H, m).

Description 15 1-[(4-iodophenyl)methyl]-2-pyrrolidinone

A solution of 2-pyrrolidinone (850 mg, 10 mmol) in dimethylformamide (40ml) was cooled in an ice/methanol bath with stirring under an atmosphereof argon. Then a solid suspension of sodium hydride (60% in mineral oil,440 mg, 11 mmol) was added portionwise over 10 minutes. The reaction mixwas allowed to stir with cooling for 30 minutes, then 4-iodobenzylbromide (2.97 g, 10 mmol) was added portionwise over 10 minutes. Thewhole mix was allowed to warm slowly up to room temperature then stirredfor a further 2 hours. The reaction mixture was partitioned betweenethyl acetate (100 ml), and water (200 ml), the organic layer wasremoved and reduced to minimum volume under reduced pressure. Theresidue was purified by column chromatography on a 20 g pre-packedsilica column eluting from 0-100% ethyl acetate in petroleum ether togive the title compound as a yellow solid (2.97 g, 99%).

LC/mass spec (ES): Found 302 (ES+), retention time 2.59 mins. C₁₁H₁₂INOrequires 301.

¹H-NMR (400 MHz, CDCl₃): 2.01 (2H, m), 2.44 (2H, t, J=8 Hz), 3.25 (2H,t, J=7 Hz), 4.39 (2H, s), 7.00 (2H, d, J=8 Hz), 7.66 (2H, m).

Description 16 5-(4-bromophenyl)-1-methyl-2-pyrrolidinone

A solution of 5-(4-bromophenyl)-2-pyrrolidinone (preparation describedin WO00/21958) (200 mg, 0.83 mmol) in dimethylformamide (5 ml) wastreated with a solid suspension of sodium hydride (60% in mineral oil,35 mg, 0.88 mmol). The reaction mix was allowed to stir for 20 minutes,then methyl iodide (124 mg, 0.88 mmol) was added and the whole mixstirred for a further 18 hours. The reaction mixture was quenched with afew drops of water then partitioned between dichloromethane (15 ml), andwater (60 ml), the organic layer was removed and washed with water again(2×10 ml), then reduced to minimum volume under reduced pressure to givethe title compound as a brown oil (141 mg, 67%).

LC/mass spec (ES): Found 254 (ES+), retention time 2.41 mins. C₁₁H₁₂⁷⁹BrNO requires 253.

¹H-NMR (400 MHz, CDCl₃): 1.85 (1H, m), 2.40-2.62 (3H, m), 2.67 (3H, s),4.48 (1H, m), 7.08 (2H, m), 7.52 (2H, m).

Description 171-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

To a solution of{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanol(Example 30, 1.23 g, 4.16 mmol) in dichloromethane (20 ml) under anatmosphere of argon was added triethylamine (0.75 ml, 5.4 mmol) and themixture stirred at room temperature for 10 minutes. Methanesulfonylchloride (0.42 ml, 5.4 mmol) was added dropwise over 5 minutes and thewhole mix stirred at room temperature for 18 hours. The reaction mixturewas then washed twice with water followed by saturated sodiumbicarbonate. The organic layer dried over sodium sulphate and thesolvent removed by rotary evaporation to give the title compound as abrown oil (1.24 g, 94%)

LC/mass spec (ES): Found 315 (ES+), retention time 3.74 mins. C₁₅H₁₄³⁵ClF₃N₂ requires 314. ¹H-NMR (400 MHz, CDCl₃): 1.83 (4H, m), 2.70 (4H,m), 4.63 (2H, s), 7.51 (4H, m).

Description 18 4-[(4-iodophenyl)carbonyl]morpholine

A solution of morpholine (653 mg, 7.5 mmol) in dichloromethane (40 ml)was cooled in an ice/methanol bath and then treated with stirring underargon with triethylamine (7.5 mmol, 1.05 ml) followed by the portionwiseaddition of 4-iodobenzoyl chloride (2.0 g, 7.5 mmol). The reaction mixwas allowed to stir at room temperature for 0.5 h before the solutionwas washed with water (2×20 ml). The organic layer was dried over sodiumsulphate and evaporated under reduced pressure to give the titlecompound as a yellow solid (2.4 g, 100%).

LC/Mass Spec (ES): Found 318 (ES+), retention time 2.36 mins. C₁₁H₁₂INO₂requires 317.

1H-NMR (400 MHz, CDCl₃): 3.32-3.94 (8H, m), 7.15 (2H, m), 7.77 (2H, m).

Description 194-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzonitrile

A mixture of 4-iodobenzonitrile (2.41 g, 10.5 mmol),3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (2.0 g, 10.5 mmol),copper (I) oxide (20 mol %, 2.1 mmol, 300 mg), N,N-dimethylglycine (10.5mmol, 1.082 g), and cesium carbonate (21 mmol, 6.84 g) indimethylsulfoxide (5 ml) was heated in an oil bath at 130° C. underargon for 4 h. The reaction mixture was diluted with ethyl acetate.Solid filtered off through kieselguhr. The filtrate was partitionedbetween ethyl acetate and water. The organic layer was separated anddried over sodium sulphate. The solvent was removed by rotaryevaporation and triturated with diethyl ether to give the title compoundas a light brown solid (1.812 g, 59.5%).

LC/Mass Spec (ES): Found 292 (ES+), retention time 3.43 mins. C₁₅H₁₂F₃N₃requires 291.

1H-NMR (400 MHz, DMSO): 1.76 (4H, m), 2.60 (2H, m), 2.82 (2H, m), 7.82(2H, m), 8.10 (2H, m).

Description 20

({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)amine

Lithium aluminium hydride (12.44 ml, 2 M in THF solution, 24.88 mmol)and THF (30 ml) were stirred in an ice bath under argon. A solution of4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzonitrile(1.812 g, 6.22 mmol) in THF (30 ml) was added dropwise over 15 mins.Then the ice bath was removed and the reaction mixture was allowed tostir at room temperature for 1.5 hrs. Then the reaction mixture wascooled using an ice bath and quenched with water dropwise, solvent wasremoved under vacuo (i.e reduced pressure). Residual material wasdiluted with DCM and water. Insoluble solid filtered off and organiclayer separated, washed with brine, dried over sodium sulphate. Thesolvent was removed by rotary evaporation. The desired product wasisolated using a 25 g SCX column initially washed with DCM (30 ml),DCM/MeOH (60 ml), MeOH (30 ml) and then the desired product was elutedwith 1M ammonia in MeOH (25 ml). Solvent evaporated off under reducedpressure to give the title compound as a brown oil (1.563 g, 85%).

LC/Mass Spec (ES): Found 279 (M-16, ES+), retention time 2.16 mins.C₁₅H₁₆F₃N₃ requires 295. 1H-NMR (400 MHz, CDCl3): 1.82 (4H, m), 2.68(4H, m), 3.93 (2H, s), 7.43 (4H, m).

Description 211-[(4-nitrophenyl)methyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

A solution of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (380mg, 2 mmol) in anhydrous DMF (10 ml) was treated with potassiumcarbonate (552 mg, 4 mmol) followed by 4-nitrobenzyl chloride (343 mg, 2mmol) and the whole mix stirred under argon for 16 h at roomtemperature. The reaction mixture was separated between water (20 ml)and ethyl acetate (20 ml). The organic layer was washed again with awater/brine mix (1:1) (10 ml) then dried over sodium sulphate and thesolvent removed under reduced pressure to give a yellow oil (751 mg)which was chromatographed on a 5 g pre-packed silica column eluting from0-20% ethyl acetate in petroleum ether to give the title compound as ayellow oil (416 mg, 64%).

LC/Mass Spec (ES): Found 326 (ES+), retention time 3.44 mins.C₁₅H₁₄F₃N₃O₂ requires 325.

Description 224-{[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]methyl}aniline

A solution of1-[(4-nitrophenyl)methyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole(410 mg, 1.26 mmol) in methanol (3 ml) was added dropwise to a stirredsuspension of 10% palladium on charcoal in water (1.3 ml) containingsodium borohydride (95 mg, 2.50 mmol), under argon with cooling. Theresulting mix was stirred at room temperature for 1 hour. The reactionmix was filtered and then acidified using 2M HCl to destroy any excesssodium borohydride, and then basified again using 2M aqueous sodiumhydroxide. The mix was partitioned between ethyl acetate and water. Theorganic layer was dried over sodium sulphate and the solvent removedunder reduced pressure to give a yellow oil, which was chromatographedon a 5 g pre-packed silica column eluting from 0-20% ethyl acetate inpetroleum ether to give the title compound as a yellow oil (166 mg,43%).

LC/Mass Spec (ES): Found 296 (ES+), retention time 2.70 mins. C₁₅H₁₆F₃N₃requires 295.

¹H-NMR (400 MHz, CDCl₃): 1.64-1.88 (4H, m), 2.43-2.68 (4H, m), 3.68 (2H,bs), 5.12 (2H, s), 6.62 (2H, m), 6.98 (2H, m).

Description 23 N-[(4-bromophenyl)methyl]-1-pyrrolidinecarboxamide

A solution of 4-bromobenzylisocyanate (408 mg, 1.92 mmol) inacetonitrile (15 ml) was treated with triethylamine (390 mg, 3.86 mmol)followed by pyrrolidine (137 mg, 1.93 mmol) at room temperature withstirring under argon. The reaction was stirred at 20° C. for 30 minutesand then partitioned between ethyl acetate (10 ml) and water (20 ml).The organic layer was dried over sodium sulphate and evaporated underreduced pressure to give the title compound as a colourless solid (542mg, 99%).

LC/Mass Spec (ES): Found 283 (ES+), retention time 2.42 mins. C₁₂H₁₅⁷⁹BrN₂O requires 282. ¹H-NMR (400 MHz, CDCl₃): 1.91 (4H, m), 3.45 (4H,m), 4.49 (2H, m), 4.51 (1H, m), 7.21 (2H, m), 7.44 (2H, m).

Description 24N-[(4-bromophenyl)methyl]-N-methyl-1-pyrrolidinecarboxamide

N-[(4-bromophenyl)methyl]-1-pyrrolidinecarboxamide (230 mg, 0.81 mmol),was dissolved in dimethylformamide (2 ml) and treated at roomtemperature with a 60% sodium hydride suspension in mineral oil (33 mg,0.83 mmol). This mix was stirred for 15 minutes before being treatedwith iodomethane (116 mg, 0.82 mmol). The resulting mix was stirred at20° C. for a total of 16.5 hours. The reaction was quenched with water(4 ml) and extracted into ethyl acetate (4 ml). The organic layer wasdried over sodium sulphate and the solvent removed under reducedpressure to give the title compound as a colourless oil (250 mg, crude).LC/Mass Spec (ES): Found 297 (ES+), retention time 2.90 mins. C₁₃H₁₇⁷⁹BrN₂O requires 296.

Description 25 N-[1-(4-bromophenyl)ethyl]acetamide

To a solution of 4-bromo-{tilde over (□)}methylbenzylamine (2.0 g, 10mmol) and triethylamine (2 g, 20 mmol, 2.8 ml), in dichloromethane (40ml) was added acetyl chloride (0.86 g, 11 mmol, 0.78 ml) dropwise withstirring under an atmosphere of argon, and the whole mix stirred at 20°C. for 0.5 hours. The reaction mixture was washed twice with water (30ml each) and the organic layer dried over sodium sulphate and thesolvent removed under reduced pressure to give the title compound as ayellow solid (2.27 g, 94%).

LC/Mass Spec (ES): Found 242 (ES+), retention time 2.24 mins. C₁₀H₁₂⁷⁹BrNO requires 241.

¹H-NMR (400 MHz, CDCl₃): 1.46 (3H, d, J=7 Hz), 1.99 (3H, s), 5.08 (1H,m), 5.67 (1H, M), 7.19 (2H, m), 7.46 (2H, m).

Description 26 N-[1-(4-bromophenyl)ethyl]-N-methylacetamide

The title compound was prepared from N-[1-(4-bromophenyl)ethyl]acetamideand iodomethane in a manner similar to that described for description24.

LC/Mass Spec (ES): Found 257 (ES+), retention time 2.53 mins. C₁₁H₁₄⁷⁹BrNO requires 256.

Description 27 1-acetyl-2-(4-bromophenyl)pyrrolidine

The title compound was prepared from 2-(4-bromophenyl)pyrrolidine andacetyl chloride using a similar procedure to that described indescription 25.

LC/Mass Spec (ES): Found 268 (ES+), retention time 2.59 mins. C₁₂H₁₄⁷⁹BrNO requires 267.

Description 28 2-[(4-bromophenyl)methyl]isothiazolidine 1,1-dioxide

A solution of 4-bromobenzylamine (1.85 g, 10 mmol) and triethylamine (2g, 20 mmol) in dimethylformamide (30 ml) was treated with3-chloropropanesulfonyl chloride (1.78 g, 10 mmol) by dropwise additionover 10 minutes with stirring under argon. This mix was stirred for 30minutes before being treated with a 60% suspension of sodium hydride inmineral oil (1.2 g, 30 mmol of NaH) portionwise and the whole mixstirred at room temperature for 3 days. The reaction mixture waspartitioned between water (50 ml) and dichloromethane (30 ml). Theorganic layer was dried over sodium sulphate and reduced to minimumvolume by rotary evaporation. The residue was added to a 20 g pre-packedsilica column and eluted from 0-50% ethyl acetate in petroleum ether togive the title compound as a yellow oil (2.72 g, 94%).

LC/Mass Spec (ES): Found 290 (ES+), retention time 2.68 mins. C₁₀H₁₂⁷⁹BrNO₂S requires 289. ¹H-NMR (400 MHz, CDCl₃): 2.32 (2H, m), 3.11 (2H,m), 3.21 (2H, m), 3.13 (2H, s), 7.24 (2H, m), 7.49 (2H, m).

Description 29 1-[2-(4-bromophenyl)ethyl]-2-pyrrolidinone

The title compound was prepared from 4-bromophenethylamine and4-chlorobutyryl chloride using a similar procedure to that described forDescription 28.

LC/Mass Spec (ES): Found 268 (ES+), retention time 2.50 mins. C₁₂H₁₄⁷⁹BrNO requires 267. ¹H-NMR (400 MHz, CDCl₃): 1.96 (2H, m), 2.35 (2H, t,J=8 Hz), 2.80 (2H, t, J=7 Hz), 3.26 (2H, m), 3.51 (2H, m), 7.10 (2H, m),7.42 (2H, m).

Description 30 4-iodo-N-(2-methylpropyl)benzenesulfonamide

A solution of (2-methylpropyl)amine (121 mg, 1.65 mmol) andtriethylamine (0.35 ml, 2.47 mmol) in DCM (10 ml) was treated with4-iodobenzenesulfonyl chloride (500 mg, 1.65 mmol) by dropwise additionover 10 minutes with stirring under argon. The reaction mixture wasstirred at room temperature for 16 hr. Then the reaction mixture waswashed with water (10 ml), separated the organic layer, dried withsodium sulphate. Solvent was removed by rotary evaporation to give thetitle compound as a white solid (517 mg, 92%).

LC/Mass Spec (ES): Found 340 (ES+), retention time 3.14 mins.C10H14INO2S requires 339. ¹H-NMR (400 MHz, CDCl3): 0.88 (6H, m), 1.72(1H, m), 2.78 (2H, m), 4.41 (1H, m) 7.56 (2H, m), 7.88 (2H, m).

Description 31 1-[(4-iodophenyl)sulfonyl]pyrrolidine

The title compound was prepared from 4-iodobenzenesulfonyl chloride andpyrrolidine using a similar procedure to that described for Description30.

LC/Mass Spec (ES): Found 338 (ES+), retention time 2.95 mins.C10H12INO2S requires 337. ¹H-NMR (400 MHz, CDCl3): 1.76 (4H, m), 3.21(4H, m), 7.53 (2H, m), 7.88 (2H, m).

Description 32 4-[(4-iodophenyl)sulfonyl]morpholine

The title compound was prepared from morpholine and4-iodobenzenesulfonyl chloride using a similar procedure to thatdescribed for Description 30.

LC/Mass Spec (ES): Found 354 (ES+), retention time 2.83 mins.C10H12INO3S requires 353. ¹H-NMR (400 MHz, CDCl3): 3.00 (4H, m), 3.75(4H, m), 7.46 (2H, m), 7.92 (2H, m).

Description 33 4-iodo-N-[2-(methyloxy)ethyl]benzenesulfonamide

The title compound was prepared from [2-(methyloxy)ethyl]amine and4-iodobenzenesulfonyl chloride using a similar procedure to thatdescribed for Description 30.

LC/Mass Spec (ES): Found 342 (ES+), retention time 2.61 mins. C9H12INO3Srequires 341. ¹H-NMR (400 MHz, CDCl3): 3.10 (2H, m), 3.27 (3H, s), 3.40(2H, m), 4.86 (1H, m), 7.56 (2H, m), 7.87 (2H, m).

Description 34 4-iodo-N-[2-(1-pyrrolidinyl)ethyl]benzenesulfonamide

The title compound was prepared from [2-(1-pyrrolidinyl)ethyl]amine and4-iodobenzenesulfonyl chloride using a similar procedure to thatdescribed for Description 30.

LC/Mass Spec (ES): Found 381 (ES+), retention time 1.69 mins.C12H17IN2O2S requires 380.

Description 35 4-iodo-N-(tetrahydro-2-furanylmethyl)benzenesulfonamide

The title compound was prepared from (tetrahydro-2-furanylmethyl)amineand 4-iodobenzenesulfonyl chloride using a similar procedure to thatdescribed for Description 30.

LC/Mass Spec (ES): Found 368 (ES+), retention time 2.70 mins.C11H14INO3S requires 367. ¹H-NMR (400 MHz, CDCl3): 1.60 (1H, m),1.83-2.0 (3H, m), 2.88 (1H, m), 3.13 (1H, m), 3.70 (1H, m), 3.77 (1H,m), 3.93 (1H, m), 4.83 (1H, m), 7.55 (2H, m), 7.86 (2H, m).

Description 36 N,1-dimethyl-N-(methyloxy)-1H-imidazole-2-carboxamide

HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) (1.75 g; 4.60 mmol) was added in on portion to astirring solution of 1-methyl-1H-imidazole-2-carboxylic acid (509 mg;4.04 mmol), N,O-dimethylhydroxylamine hydrochloride (391 mg; 4.01 mmol),and diisopropylethylamine (2.0 mL; 11.9 mmol) in anhydrous DMF (14 mL).The mixture was stirred at room temperature for 17 hours and partitionedbetween ethyl acetate (100 mL) and water (100 mL). The organic phase wasdried (MgSO₄) and concentrated in vacuo, giving a colourless oil (1.45g). This was purified by column chromatography, giving the titlecompound as a colourless oil (494 mg; 73%).

¹H-NMR (400 MHz, CDCl₃): 3.57 (3H, br s), 3.86 (3H, s), 3.91 (3H, s),6.97 (1H, d, J=1 Hz), 7.07 (1H, d, J=1 Hz).

Description 37N-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-1-pyrrolidinecarboxamide

Diphenylphosphoryl azide (290 μL; 1.36 mmol) was added in one portion toa stirring mixture of4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid(195 mg; 0.63 mmol) and diisopropylethylamine (220 μL; 1.29 mmol) in1,4-dioxane (2.2 mL). The mixture was heated at reflux for 2 hours,pyrrolidine (100 μL; 1.21 mmol) was added in on portion, and thereaction heated at reflux for a further 1 hour. Concentration in vacuo,followed by column chromatography gave the title compound (38 mg; 16%).

LC/Mass Spec (ES): found 379 (ES+), retention time 3.18 mins.C₁₉H₂₁F₃N₄O requires 378. ¹H-NMR (400 MHz, CDCl₃): 1.67-1.77 (4H, m),1.83-2.03 (4H, m), 2.68-2.77 (4H, m), 3.40-3.54 (4H, m), 6.34 (1H, s),7.34-7.40 (2H, m), 7.50-7.55 (2H, m).

EXAMPLE 1N,N-dimethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide

A mixture of 4-iodo-N,N-dimethylbenzamide (100 mg, 0.36 mmol),3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (83 mg, 0.44 mmol),copper (I) iodide (1 mol %, 0.7 mg, 0.0036 mmol),trans-1,2-diaminocyclohexane (10 mol %, 4 mg, 0.036 mmol) and potassiumcarbonate (105 mg, 0.76 mmol) in 1,4-dioxane (0.5 ml) was stirred at180° C. in a microwave reactor for 15 minutes, then fresh copper (I)iodide (1 mol %, 0.7 mg, 0.0036 mmol) and trans-1,2-diaminocyclohexane(10 mol %, 4 mg, 0.036 mmol) were added and the reaction stirred at 180°C. in a microwave reactor for 20 minutes. Then fresh copper (I) iodide(1 mol %, 0.7 mg, 0.0036 mmol) and trans-1,2-diaminocyclohexane (10 mol%, 4 mg, 0.036 mmol) were added and the reaction stirred at 180° C. in amicrowave reactor for 30 minutes. The reaction mix was cooled and addedto a 5 g pre-packed silica column which was then eluted from ethylacetate, the product was further purified by mass directed auto-prep togive a crop of the title compound as a brown oil (53 mg, 43%).

LC/mass spec (ES): Found 338 (ES+), retention time 3.09 mins.C₁₇H₁₈F₃N₃O requires 337. ¹H-NMR (400 MHz, CDCl₃): 1.83 (4H, m), 2.70(4H, m), 3.00 (3H, s), 3.14 (3H, s), 7.54 (4H, m).

EXAMPLE 21-[4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

A solution of4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid(87 mg, 0.28 mmol) in dichloromethane (3 ml) was treated in one portionwith solid 1,1′-carbonyldiimidazole (46 mg, 0.28 mmol). This mixture wasallowed to stir at room temperature for 15 minutes. Pyrrolidine (23 mg,0.32 mmol) was then added and the stirring continued for 1 hour at roomtemperature. The reaction mixture was then added to a 5 g pre-packedsilica column and eluted from 0-50% ethyl acetate in petroleum ether togive the title compound as a yellow oil (51 mg, 50%).

LC/mass spec (ES): Found 364 (ES+), retention time 3.22 mins.C₁₉H₂₀F₃N₃O requires 363. ¹H-NMR (400 MHz, CDCl₃): 1.83 (4H, m), 1.91(2H, m), 1.98 (2H, m), 2.70 (4H, m), 3.43 (2H, t, J=6 Hz), 3.67 (2H, t,J=6 Hz), 7.53 (2H, m), 7.64 (2H, m).

EXAMPLE 3N-methyl-N-(phenylmethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide

The title compound was prepared from4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acidand N-methylbenzylamine using a similar procedure to that described forExample 2.

LC/mass spec (ES): Found 414 (ES+), retention time 3.71 mins.C₂₃H₂₂F₃N₃O requires 413. ¹H-NMR (400 MHz, CDCl₃): 1.82 (4H, m), 2.69(4H, m), 2.88 & 3.07 (3H, s (rotomers)), 4.52 & 4.77 (2H, s (rotomers)),7.17 (1H, m), 7.34 (4H, m), 7.55 (4H, m).

EXAMPLE 4N-ethyl-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide

The title compound was prepared from4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acidand N-ethylmethylamine using a similar procedure to that described forExample 2.

LC/mass spec (ES): Found 352 (ES+), retention time 3.22 mins.C₁₈H₂₀F₃N₃O requires 351. ¹H-NMR (400 MHz, CDCl₃): 1.07-1.28 (3H, m(rotomers)), 1.83 (4H, m), 2.70 (4H, m), 2.96 & 3.09 (3H, m (rotomers)),3.31 & 3.61 (2H, m (rotomers)), 7.53 (4H, m).

EXAMPLE 5N-butyl-N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide

The title compound was prepared from4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acidand N-methylbutylamine using a similar procedure to that described forExample 2.

LC/mass spec (ES): Found 380 (ES+), retention time 3.54 mins.C₂₀H₂₄F₃N₃O requires 379. ¹H-NMR (400 MHz, CDCl₃): 0.81-1.01 (3H, m(rotomers)), 1.17 & 1.42 (2H, m (rotomers)), 1.53-1.63 (2H, m) 1.83 (4H,m), 2.70 (4H, m), 2.95 & 3.09 (3H, m (rotomers)), 3.24 & 3.55 (2H, m(rotomers)), 7.53 (4H, m).

EXAMPLE 6N-methyl-N-(2-phenylethyl)-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide

The title compound was prepared from4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acidand N-methylphenethylamine using a similar procedure to that describedfor Example 2.

LC/mass spec (ES): Found 428 (ES+), retention time 3.70 mins.C₂₄H₂₄F₃N₃O requires 427. ¹H-NMR (400 MHz, CDCl₃): 1.82 (4H, m), 2.68(4H, m), 2.83 (3H, s), 3.00 & 3.16 (2H, m (rotomers)), 3.51 & 3.80 (2H,m (rotomers)), 6.98 (1H, m), 7.12 (1H, m), 7.28 (4H, m), 7.43 (2H, m),7.52 (1H, m).

EXAMPLE 7N,N-dimethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzenesulfonamide

A mixture of 4-iodo-N,N-dimethylbenzenesulfonamide (156 mg, 0.5 mmol),3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (105 mg, 0.55 mmol),copper (I) iodide (1 mol %, 1 mg, 0.005 mmol),trans-1,2-diaminocyclohexane (10 mol %, 6 mg, 0.05 mmol) and potassiumcarbonate (145 mg, 1.05 mmol) in 1,4-dioxane (1 ml) was stirred at 180°C. in a microwave reactor for 45 minutes. The reaction mix was cooledand added to a 5 g pre-packed silica column which was then eluted fromethyl acetate, the product was further purified by mass directedauto-prep to give a crop of the title compound as a pale beige solid (65mg, 35%).

LC/mass spec (ES): Found 374 (ES+), retention time 3.55 mins.C₁₆H₁₈F₃N₃O₂S requires 373. ¹H-NMR (400 MHz, CDCl₃): 1.85 (4H, m), 2.70(2H, m), 2.74 (6H, s), 2.77 (2H, m), 7.72 (2H, m), 7.89 (2H, m).

EXAMPLE 81-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}ethanone

The title compound was prepared from 4-iodoacetophenone and3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similarprocedure to that described for Example 7.

LC/mass spec (ES): Found 309 (ES+), retention time 3.52 mins.C₁₆H₁₅F₃N₂O requires 308. ¹H-NMR (400 MHz, CDCl₃): 1.84 (4H, m), 2.64(3H, s), 2.70 (2H, m), 2.77 (2H, m), 7.64 (2H, m), 8.07 (2H, m).

EXAMPLE 91-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-1-propanone

The title compound was prepared from 1-(4-bromophenyl)-1-propanone and3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similarprocedure to that described for Example 1.

LC/mass spec (ES): Found 323 (ES+), retention time 3.75 mins.C₁₇H₁₇F₃N₂O requires 322. ¹H-NMR (400 MHz, CDCl₃): 1.25 (3H, t, J=7 Hz),1.84 (4H, m), 2.69 (2H, m), 2.78 (2H, m), 3.04 (2H, quart., J=7 Hz),7.63 (2H, m), 8.07 (2H, m).

EXAMPLE 101-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

The title compound was prepared from 4-bromophenyl methyl sulfone and3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similarprocedure to that described for Example 7.

LC/mass spec (ES): Found 345 (ES+), retention time 3.26 mins.C₁₅H₁₅F₃N₂O₂S requires 344. ¹H-NMR (400 MHz, CDCl₃): 1.86 (4H, m), 2.70(2H, m), 2.80 (2H, m), 3.10 (3H, s), 7.76 (2H, m), 8.06 (2H, m).

EXAMPLE 111-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-2-propanone

The title compound was prepared from 4-bromophenylacetone and3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similarprocedure to that described for Example 7.

LC/mass spec (ES): Found 323 (ES+), retention time 3.44 mins.C₁₇H₁₇F₃N₂O requires 322. ¹H-NMR (400 MHz, CDCl₃): 1.82 (4H, m), 2.19(3H, s), 2.69 (4H, m), 3.76 (2H, s), 7.30 (2H, m), 7.46 (2H, m).

EXAMPLE 12N,N-dimethyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide

The title compound was prepared from2-(4-bromophenyl)-N,N-dimethylacetamide and3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similarprocedure to that described for Example 7.

LC/mass spec (ES): Found 352 (ES+), retention time 3.15 mins.C₁₈H₂₀F₃N₃O requires 351. ¹H-NMR (400 MHz, CDCl₃): 1.81 (4H, m), 2.69(4H, m), 2.99 (3H, s), 3.02 (3H, s), 3.76 (2H, s), 7.35 (2H, d, J=8 Hz),7.43 (2H, m).

EXAMPLE 131-{4-[2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

A solution of{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}aceticacid (113 mg, 0.35 mmol) in dichloromethane (4 ml) in a sarstedt tubewas treated in one portion with solid 1,1′-carbonyldiimidazole (60 mg,0.37 mmol). This mixture was shaken at room temperature for 30 minutes.Pyrrolidine (34 mg, 0.48 mmol) in dichloromethane (2 ml) was then addedand the shaking continued for 16 hour at room temperature. The reactionmixture was washed with a mix of saturated sodium bicarbonate solution(4 ml) and brine (2 ml). The organic layer was then added to a 2 g SCXcolumn and eluted with ethyl acetate (25 ml), the solvent removed underreduced pressure and the residue purified by mass directed auto-prep togive the title compound as a yellow oil (30 mg, 23%).

LC/mass spec (ES): Found 378 (ES+), retention time 3.28 mins.C₂₀H₂₂F₃N₃O requires 377. ¹H-NMR (400 MHz, CDCl₃): 1.81 (4H, m), 1.88(2H, m), 1.96 (2H, m), 2.69 (4H, m), 3.44 (2H, t, J=7 Hz), 3.50 (2H, t,J=7 Hz), 3.71 (2H, s), 7.38 (2H, d, J=8 Hz), 7.43 (2H, m).

EXAMPLE 14N-ethyl-N-methyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide

The title compound was prepared from{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}aceticacid and N-ethylmethylamine using a similar procedure to that describedfor Example 13, but purified by flash column chromatography eluting from0-100% ethyl acetate in hexane.

LC/mass spec (ES): Found 366 (ES+), retention time 3.28 mins.C₁₉H₂₂F₃N₃O requires 365. ¹H-NMR (400 MHz, CDCl₃): 1.12 (3H, m), 1.82(4H, m), 2.68 (4H, m), 2.95 & 2.97 (3H, s (rotomers)), 3.34-3.47 (2H, m(rotomers)), 3.75 (2H, m), 7.36 (2H, m), 7.44 (2H, d, J=8 Hz).

EXAMPLE 15N-methyl-N-(phenylmethyl)-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide

The title compound was prepared from{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}aceticacid and N-methylbenzylamine using a similar procedure to that describedfor Example 13, but purified by flash column chromatography eluting from0-66% ethyl acetate in hexane.

LC/mass spec (ES): Found 428 (ES+), retention time 3.55 mins.C₂₄H₂₄F₃N₃O requires 427. ¹H-NMR (400 MHz, CDCl₃): 1.82 (4H, m), 2.69(4H, m), 2.93 & 2.99 (3H, s, (rotomers)), 3.78 & 3.82 (2H, s,(rotomers)), 4.55 & 4.62 (2H, s, (rotomers)), 7.12-7.46 (9H, m).

EXAMPLE 16N-butyl-N-methyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide

The title compound was prepared from{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}aceticacid and N-methylbutylamine using a similar procedure to that describedfor Example 13, but purified by flash column chromatography eluting from0-66% ethyl acetate in hexane.

LC/mass spec (ES): Found 394 (ES+), retention time 3.63 mins.C₂₁H₂₆F₃N₃O requires 393.

¹H-NMR (400 MHz, CDCl₃): 0.94 (3H, m), 1.24-1.35 (2H, m), 1.47-1.55 (2H,m), 1.82 (4H, m), 2.68 (4H, m), 2.95 & 2.97 (3H, s (rotomers)), 3.28 &3.39 (2H, m (rotomers)), 3.75 (2H, m), 7.36 (2H, d, J=8 Hz), 7.43 (2H,d, J=8 Hz)

EXAMPLE 17N-methyl-N-(2-phenylethyl)-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide

The title compound was prepared from{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}aceticacid and N-methylphenethylamine using a similar procedure to thatdescribed for Example 13, but purified by flash column chromatographyeluting from 0-88% ethyl acetate in hexane, followed by mass directedauto-prep.

LC/mass spec (ES): Found 442 (ES+), retention time 3.58 mins.C₂₅H₂₆F₃N₃O requires 441.

¹H-NMR (400 MHz, CDCl₃): 1.81 (4H, m), 2.68 (4H, m), 2.83 (2H, m), 2.89& 3.01 (3H, s (rotomers)), 3.41 & 3.73 (2H, s (rotomers)), 3.54 & 3.63(2H, t, J=7 Hz (rotomers)), 7.17 (3H, m), 7.29 (4H, m), 7.42 (2H, m).

EXAMPLE 181-{[4-(1-pyrrolidinylcarbonyl)phenyl]methyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

A mixture of 1-{[4-(bromomethyl)phenyl]carbonyl}pyrrolidine (84 mg, 0.31mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (60 mg, 0.32mmol), and potassium carbonate (87 mg, 0.63 mmol) inN,N-dimethylformamide (2 ml) was stirred at 140° C. in a microwavereactor for 10 minutes. The reaction mixture was cooled and partitionedbetween dichloromethane and water. The organic layer was dried oversodium sulphate and reduced to minimum volume under reduced pressure.The crude product was purified using mass directed auto-prep to give thetitle compound as a pale yellow oil (63 mg, 54%).

LC/mass spec (ES): Found 378 (ES+), retention time 3.11 mins.C₂₀H₂₂F₃N₃O requires 377.

¹H-NMR (400 MHz, CDCl₃): 1.69-1.80 (4H, m), 1.87 (2H, m), 1.96 (2H, m),2.43 (2H, m), 2.60 (2H, m), 3.40 (2H, t, J=7 Hz), 3.64 (2H, t, J=7 Hz),5.27 (2H, s), 7.13 (2H, d, J=8 Hz), 7.48 (2H, dd, J=6 Hz, & 2 Hz).

EXAMPLE 191-{4-[1-methyl-2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

A mixture of 1-[2-(4-bromophenyl)propanoyl]pyrrolidine (140 mg, 0.5mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (95 mg, 0.5mmol), copper (I) iodide (10 mol %, 10 mg, 0.05 mmol),N,N-dimethylglycine (20 mol %, 10 mg, 0.1 mmol) and potassium carbonate(138 mg, 1 mmol) in dimethylsulfoxide (2 ml) was stirred at 190° C. in amicrowave reactor for a total of 1.5 h. The reaction mix was cooled andpartitioned between ethyl acetate and water. The organic layer was driedover sodium sulphate and the solvent removed under reduced pressure. Theresulting product was purified firstly by adding the material indichloromethane to a 5 g pre-packed silica column and eluting with ethylacetate, followed by mass directed auto-prep to give a crop of the titlecompound as a brown oil (8 mg, 4%).

LC/mass spec (ES): Found 392 (ES+), retention time 3.45 mins.C₂₁H₂₄F₃N₃O requires 391.

¹H-NMR (400 MHz, CDCl₃): 1.47 (3H, d, J=7 Hz), 1.74-1.92 (8H, m), 2.69(4H, m), 3.17 (1H, m), 3.40-3.57 (3H, m), 3.79 (1H, m), 7.40 (4H, m).

EXAMPLE 20N,N-dimethyl-3-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}propanamide

The title compound was prepared from3-(4-bromophenyl)-N,N-dimethylpropanamide and3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similarprocedure to that described for Example 1.

LC/mass spec (ES): Found 366 (ES+), retention time 3.23 mins.C₁₉H₂₂F₃N₃O requires 365.

¹H-NMR (400 MHz, CDCl₃): 1.82 (4H, m), 2.63 (2H, t, J=8 Hz), 2.67 (4H,m), 2.96 (6H, s), 3.02 (2H, t, J=8 Hz), 7.32 (2H, d, J=8 Hz), 7.39 (2H,m).

EXAMPLE 211-{4-[3-oxo-3-(1-pyrrolidinyl)propyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

The title compound was prepared from1-[3-(4-bromophenyl)propanoyl]pyrrolidine and3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similarprocedure to that described for Example 19.

LC/mass spec (ES): Found 392 (ES+), retention time 3.40 mins.C₂₁H₂₄F₃N₃O requires 391.

¹H-NMR (400 MHz, CDCl₃): 1.81 (4H, m), 1.85 (2H, m), 1.92 (2H, m), 2.58(2H, m), 2.64 (4H, m), 3.04 (2H, t, J=8 Hz), 3.33 (2H, t, J=7 Hz), 3.47(2H, t, J=7 Hz), 7.32 (2H, m), 7.39 (2H, m).

EXAMPLE 221-{4-[1-(1-pyrrolidinylcarbonyl)cyclopropyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

The title compound was prepared from1-{[1-(4-iodophenyl)cyclopropyl]carbonyl}pyrrolidine and3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similarprocedure to that described for Example 19.

LC/mass spec (ES): Found 404 (ES+), retention time 3.43 mins.C₂₂H₂₄F₃N₃O requires 403.

¹H-NMR (400 MHz, CDCl₃): 1.18 (2H, m), 1.48 (2H, m), 1.75-1.83 (8H, m),2.68 (4H, m), 3.19 (2H, m), 3.49 (2H, m), 7.28 (2H, m), 7.41 (2H, m).

EXAMPLE 231-{4-[2-oxo-2-(1-piperidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

The title compound was prepared from{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}aceticacid and piperidine using a similar procedure to that described forExample 2, product further purified by mass directed auto-prep.

LC/mass spec (ES): Found 392 (ES+), retention time 3.45 mins.C₂₁H₂₄F₃N₃O requires 391.

¹H-NMR (400 MHz, CDCl₃): 1.41 (2H, m), 1.53 (2H, m), 1.59 (2H, m), 1.82(4H, m), 2.68 (4H, m), 3.39 (2H, m), 3.58 (2H, m), 3.77 (2H, s), 7.36(2H, m), 7.44 (2H, m).

EXAMPLE 241-{4-[2-(3,3-difluoro-1-pyrrolidinyl)-2-oxoethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

A solution of{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}aceticacid (65 mg, 0.2 mmol) in dichloromethane (2 ml) was treated in oneportion with solid 1,1′-carbonyldiimidazole (33 mg, 0.2 mmol). Thismixture was allowed to stir at room temperature for 15 minutes.3,3-difluoropyrrolidine hydrochloride (29 mg, 0.2 mmol) was then addedfollowed by triethylamine (21 mg, 0.21 mmol) and the stirring continuedfor 1 hour at room temperature. The reaction mixture was reduced tominimum volume under reduced pressure then purified by mass directedauto-prep to give the title compound as a yellow oil (53 mg, 64%).

LC/mass spec (ES): Found 414 (ES+), retention time 3.34 mins.C₂₀H₂₀F₅N₃O requires 413.

¹H-NMR (400 MHz, CDCl₃): 1.82 (4H, m), 2.35 (1H, m), 2.43 (1H, m), 2.69(4H, m), 3.67-3.87 (6H, m), 7.36 (2H, m), 7.46 (2H, m).

EXAMPLE 25N-methyl-N-propyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide

The title compound was prepared from{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}aceticacid and N-methylpropylamine using a similar procedure to that describedfor Example 2, product further purified by mass directed auto-prep.

LC/mass spec (ES): Found 380 (ES+), retention time 3.41 mins.C₂₀H₂₄F₃N₃O requires 379.

¹H-NMR (400 MHz, CDCl₃): 0.89 (3H, m), 1.56 (2H, m), 1.81 (4H, m), 2.68(4H, m), 2.96 (3H, m), 3.26 (1H, m), 3.36 (1H, m), 3.76 (2H, m), 7.36(2H, d, J=9 Hz), 7.44 (2H, d, J=8 Hz).

EXAMPLE 26N-cyclopentyl-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide

The title compound was prepared from{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}aceticacid and cyclopentylamine using a similar procedure to that describedfor Example 2, except product was purified by mass directed auto-prep.

LC/mass spec (ES): Found 392 (ES+), retention time 3.37 mins.C₂₁H₂₄F₃N₃O requires 391.

¹H-NMR (400 MHz, CDCl₃): 1.26 (2H, m), 1.53-1.63 (4H, m), 1.82 (4H, m),1.92-2.00 (2H, m), 2.70 (4H, m), 3.58 (2H, s), 4.20 (1H, m), 5.29 (1H,m), 7.36 (2H, d, J=8 Hz), 7.48 (2H, m).

EXAMPLE 27N-methyl-N-(2-thienylmethyl)-2-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetamide

A solution of{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}aceticacid (65 mg, 0.2 mmol) in dichloromethane (2 ml) was treated in oneportion with solid 1,1′-carbonyldiimidazole (33 g, 0.2 mmol). Thismixture was shaken at room temperature for 15 minutes.Methylthiophen-2-yl methylamine (25 mg, 0.2 mmol) was then added and theshaking continued for 1 hour at room temperature. The reaction mixturewas partitioned between dichloromethane and saturated sodium bicarbonatesolution (3 ml). The organic layer was dried over sodium sulphate andevaporated under reduced pressure to give a yellow oil which waspurified using mass directed auto-prep to give the title compound as ayellow oil (42 mg, 48%).

LC/mass spec (ES): Found 434 (ES+), retention time 3.54 mins.C₂₂H₂₂F₃N₃OS requires 433.

¹H-NMR (400 MHz, CDCl₃): 1.82 (4H, m), 2.69 (4H, m), 2.97 & 3.01 (3H, s(rotomers)), 3.79 & 3.86 (2H, s, (rotomers)), 4.66 & 4.74 (2H, s(rotomers)), 6.89-6.99 (2H, m), 7.23 (1H, m), 7.36 (2H, m), 7.44 (2H,m).

EXAMPLE 28{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetonitrile

The title compound was prepared from (4-bromophenyl)acetonitrile and3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similarprocedure to that described for Example 7.

LC/mass spec (ES): Found 306 (ES+), retention time 3.34 mins. C₁₆H₁₄F₃N₃requires 305.

¹H-NMR (400 MHz, CDCl₃): 1.83 (4H, m), 2.70 (4H, m), 3.82 (2H, s), 7.44(2H, d, J=8 Hz), 7.53 (2H, m).

EXAMPLE 29{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanol

A mixture of 4-iodobenzylalcohol (1.23 g, 5.25 mmol),3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (950 mg, 5 mmol),copper (I) iodide (10 mol %, 95 mg, 0.5 mmol), N,N-dimethylglycine (20mol %, 103 mg, 1 mmol) and potassium carbonate (1.45 g, 10.5 mmol) indimethylsulfoxide (30 ml) was stirred at 130° C. in an oil bath for 23h. The reaction mix was cooled and partitioned between dichloromethane(30 ml) and brine (150 ml). The organic layer was removed filtered andthe solvent removed under reduced pressure. The resulting product waspurified by flash column chromatography on a Biotage 40+M column elutingfrom 0-60% ethyl acetate in pentane to give the title compound as ayellow oil (1.27 g, 86%).

LC/mass spec (ES): Found 297 (ES+), retention time 3.06 mins.C₁₅H₁₅F₃N₂O requires 296.

¹H-NMR (400 MHz, CDCl₃): 1.76 (1H, t, J=6 Hz), 1.82 (4H, m), 2.69 (4H,m), 4.77 (2H, m), 7.48 (4H, m).

EXAMPLE 30N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide

The title compound was prepared fromN-[(4-bromophenyl)methyl]-N-methylacetamide and3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similarprocedure to that described for Example 1.

LC/mass spec (ES): Found 352 (ES+), retention time 3.13 mins.C₁₈H₂₀F₃N₃O requires 351.

¹H-NMR (400 MHz, CDCl₃): 1.82 (4H, m), 2.18 (3H, m), 2.66 (4H, m), 2.94& 2.96 (3H, s (rotomers)), 4.58 & 4.63 (2H, s (rotomers)), 7.26-7.35(2H, m (rotomers), 7.42-7.52 (2H, m (rotomers)).

EXAMPLE 311-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-pyrrolidinone

The title compound was prepared from1-[(4-iodophenyl)methyl]-2-pyrrolidinone and3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similarprocedure to that described for Example 19.

LC/mass spec (ES): Found 364 (ES+), retention time 3.18 mins.C₁₉H₂₀F₃N₃O requires 363.

¹H-NMR (400 MHz, CDCl₃): 1.82 (4H, m), 2.02 (2H, m), 2.45 (2H, m), 2.69(4H, m), 3.26 (2H, m), 4.50 (2H, m), 7.34 (2H, d, J=8 Hz), 7.45 (2H, m).

EXAMPLE 32N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)propanamide

The title compound was prepared from1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazoleand N-methylpropanamide using a similar procedure to that described forDescription 15.

LC/mass spec (ES): Found 366 (ES+), retention time 3.30 mins.C₁₉H₂₂F₃N₃O requires 365.

¹H-NMR (400 MHz, CDCl₃): 1.20 (3H, m), 1.80 (4H, m), 2.41 (2H, m), 2.68(4H, m), 2.93 & 2.97 (3H, s (rotomers)), 4.58 & 4.64 (2H, s (rotomers)),7.25-7.35 (2H, m), 7.42-7.51 (2H, m).

EXAMPLE 33N-ethyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)acetamide

The title compound was prepared from1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazoleand N-ethylacetamide using a similar procedure to that described forDescription 15.

LC/mass spec (ES): Found 366 (ES+), retention time 3.28 mins.C₁₉H₂₂F₃N₃O requires 365.

¹H-NMR (400 MHz, CDCl₃): 1.14 (3H, m), 1.82 (4H, m), 2.12 & 2.20 (3H, s(rotomers)), 2.68 (4H, m), 3.29 & 3.44 (2H, quart., J=7 Hz (rotomers)),4.57 & 4.63 (2H, s, (rotomers)), 7.29 & 7.34 (2H, d, J=8 Hz (rotomers)),7.42 & 7.50 (2H, d, J=8 Hz (rotomers)).

EXAMPLE 341-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-piperidinone

The title compound was prepared from1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazoleand 2-piperidinone using a similar procedure to that described forDescription 15.

LC/mass spec (ES): Found 378 (ES+), retention time 3.29 mins.C₂₀H₂₂F₃N₃O requires 377.

¹H-NMR (400 MHz, CDCl₃): 1.79 (8H, m), 2.48 (2H, m), 2.68 (4H, m), 3.20(2H, m), 4.64 (2H, s), 7.36 (2H, d, J=8 Hz), 7.43 (2H, m).

EXAMPLE 351-methyl-5-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-2-pyrrolidinone

A mixture of 5-(4-bromophenyl)-1-methyl-2-pyrrolidinone (141 mg, 0.56mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (111 mg, 0.58mmol), copper (I) iodide (10 mol %, 11 mg, 0.06 mmol),N,N-dimethylglycine (20 mol %, 12 mg, 0.12 mmol) and potassium carbonate(162 mg, 1.17 mmol) in dimethylsulfoxide (3 ml) was stirred at 180° C.in a microwave reactor for a total of 2 h. The reaction mix was filteredthrough a 5 g pre-packed silica column washing through withdichloromethane (20 ml), the filtrate was washed with water (50 ml) andthe organic layer dried over sodium sulphate. The solvent was removed byrotary evaporation and the sample purified by mass directed auto prep.The final product was partitioned between dichloromethane (3 ml) andwater (3 ml). The organic layer was separated and solvent removed byrotary evaporation to give the title compound as a brown oil (14 mg, 7%)

LC/mass spec (ES): Found 364 (ES+), retention time 3.14 mins.C₁₉H₂₀F₃N₃O requires 363.

¹H-NMR (400 MHz, CDCl₃): 1.88 (5H, m), 2.44-2.65 (3H, m), 2.71 (7H, m),4.58 (1H, m), 7.30 (2H, m), 7.52 (2H, m).

EXAMPLES 36-44

Typical procedure: To polymer supported1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.1 mmol, 0.068 g, 1.42mmol/g) was added a solution of 1-hydroxy-7-azabenzotriazole (0.01 mmol,0.8 ml (tetrahydrofuran:dichloromethane 1:1)) followed by the additionof 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoicacid (0.01 g, 0.05 mmol) in 1:3 N-methyl-2-pyrrolidinone:tetrahydrofuranthen the addition of the amine (0.05 mmol) in dichloromethane (0.25 ml).The reaction was allowed to mix for 60 h. Following this was addedpolymer supported isocyanate (0.068 g, 0.1 mmol, 1.5 mmol/g) and polymersupported carbonate (0.068 g, 0.1 mmol, 1.5 mmol/g) and allowed to mixfor a further 24 hours. The reaction mix was filtered and the solventremoved in the Genevac. All products were further purified by massdirected auto-prep. Example n Ar Name LC/mass spec (ES) 36 31-imidazolyl N-[3-(1H-imidazol-1- Found 432 (ES+), retentionyl)propyl]-N-methyl- time 2.67 mins. 4-[3-(trifluoromethyl)- C₂₂H₂₄F₃N₅Orequires 431. 4,5,6,7-tetrahydro- 1H-indazol-1- yl]benzamide 37 22-thienyl N-methyl-N-[2-(2- Found 434 (ES+), retentionthienyl)ethyl]-4-[3- time 3.60 mins. (trifluoromethyl)- C₂₂H₂₂F₃N₃OSrequires 4,5,6,7-tetrahydro- 433. 1H-indazol-1- yl]benzamide 38 21-(1,2,4-triazole) N-methyl-N-[2-(1H- Found 419 (ES+), retention1,2,4-triazol-1- time 3.01 mins. yl)ethyl]-4-[3- C₂₀H₂₁F₃N₆O requires418. (trifluoromethyl)- 4,5,6,7-tetrahydro- 1H-indazol-1- yl]benzamide39 1 2-(1,3-thiazole) N-methyl-N-(1,3- Found 421 (ES+), retentionthiazol-2-ylmethyl)-4- time 3.44 mins. [3-(trifluoromethyl)-C₂₀H₁₉F₃N₄OS requires 4,5,6,7-tetrahydro- 420. 1H-indazol-1-yl]benzamide 40 2 2-(1- N-methyl-N-[2-(1- Found 431 (ES+), retentionmethylpyrrole) methyl-1H-pyrrol-2- time 3.49 mins. yl)ethyl]-4-[3-C₂₃H₂₅F₃N₄O requires 430. (trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indazol-1- yl]benzamide 41 1 2-thienyl N-methyl-N-(2- Found 420(ES+), retention thienylmethyl)-4-[3- time 3.68 mins. (trifluoromethyl)-C₂₁H₂₀F₃N₃OS requires 4,5,6,7-tetrahydro- 419. 1H-indazol-1-yl]benzamide 42 1 3-pyridyl N-methyl-N-(3- Found 415 (ES+), retentionpyridinylmethyl)-4-[3- time 2.79 mins. (trifluoromethyl)- C₂₂H₂₁F₃N₄Orequires 414. 4,5,6,7-tetrahydro- 1H-indazol-1- yl]benzamide 43 12-furanyl N-(2-furanylmethyl)- Found 404 (ES+), retention N-methyl-4-[3-time 3.50 mins. (trifluoromethyl)- C₂₁H₂₀F₃N₃O₂ requires 403.4,5,6,7-tetrahydro- 1H-indazol-1- yl]benzamide 44 1 1-(4-F)phenyl N-[(4-Found 432 (ES+), retention fluorophenyl)methyl]- time 3.63 mins.N-methyl-4-[3- C₂₃H₂₁F₄N₃O requires 431. (trifluoromethyl)4,5,6,7-tetrahydro- 1H-indazol-1- yl]benzamide

EXAMPLE 451-[4-(4-morpholinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

A mixture of 4-[(4-iodophenyl)carbonyl]morpholine (1.90 g, 6.0 mmol),3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (1.14 g, 6.0 mmol),copper (I) oxide (10 mol %, 0.6 mmol, 86 mg), N,N-dimethylglycine (20mol %, 1.2 mmol, 124 mg), and cesium carbonate (12.0 mmol, 3.91 g) indimethylsulfoxide (16 ml) was stirred in an oilbath heated at 130° C.for 24 h under argon and then allowed to cool to room temperature. Thereaction mixture was partitioned between dichloromethane (30 ml) andwater (30 ml). The organic layer was separated and dried over sodiumsulphate. The solvent was removed by rotary evaporation to give a darkbrown residue that was added to a 20 g isolute pre-packed silica columnand eluted from 0-50% ethyl acetate in petroleum ether to give the titlecompound as a brown gum (1.86 g, 82%).

LC/Mass Spec (ES): Found 380 (ES+), retention time 3.07 mins.C₁₉H₂₀F₃N₃O₂ requires 379.

¹H-NMR (400 MHz, CDCl3): 1.84 (4H, m), 2.71 (4H, m), 3.36-3.90 (8H, m),7.53 (2H, m), 7.58 (2H, m).

EXAMPLE 46N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)methanesulfonamide

A mixture of({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)amine(1.563 g, 5.29 mmol), triethylamine (1.48 ml, 10.58 mmol) indichloromethane (40 ml) was stirred under argon in an ice bath.Methanesulfonyl chloride (1.213 g, 0.82 ml, 10.58 mmol) was addeddropwise with stirring. The resulting mixture was allowed to stir atroom temperature for 5 h. Then the reaction mixture was partitionedbetween dichloromethane and water. The organic layer was separated anddried over sodium sulphate. The desired product was isolated by columnchromatography on silica using 10 to 70% ethyl acetate in n-pentane togive an oil which was then triturated with n-pentane to give the titlecompound as a white solid (1.602 g, 81%).

LC/Mass Spec (ES): Found 374 (ES+), retention time 3.12 mins.C₁₆H₁₈F₃N₃O₂S requires 373.

1H-NMR (400 MHz, CDCl3): 1.82 (4H, m), 2.68 (4H, m), 2.92 (3H, s), 4.38(2H, d, J=6 Hz), 4.70 (1H, m), 7.43-7.54 (4H, m).

EXAMPLES 47-48

A solution of lithium diisopropylamide (2M in THF, 0.5 ml) in THF (5 ml)was cooled to −78° C. in a CO₂/methanol bath with stirring under argon.A solution of1-{4-[2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole(150 mg, 0.4 mmol) in THF (0.5 ml) was then added dropwise under argon.The resulting mix was stirred at −78° C. for 1 hour. Then a solution of2-fluoro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (189mg, 0.88 mmol) in THF (5 ml) was added. The resulting mix was stirred at−78° C. for 1 hour and then allowed to warm up slowly to roomtemperature. The reaction mix was quenched with saturated aqueousammonium chloride solution and partitioned between ethyl acetate andsaturated aqueous ammonium chloride. The organic layer was dried oversodium sulphate and evaporated in vaccuo (i.e under reduced pressure) togive a brown oil (260 mg) which was purified by mass directed auto prepto separate the mono (example 47) and bis (example 48) fluorinatedproducts. LC/Mass Spec 1H-NMR Ex R Name (ES) (400 MHz, CDCl₃) 47 H1-{4-[1-fluoro-2-oxo-2-(1- Found 396 1.84 (8H, m), 2.70 (4H,pyrrolidinyl)ethyl]phenyl}-3- (ES+), retention m), 3.33 (1H, m),(trifluoromethyl)-4,5,6,7- time 3.28 mins. 3.45 (1H, m), 3.56 (2H, m),tetrahydro-1H-indazole C₂₀H₂₁F₄N₃O 5.92 & 6.04 (1H, m), requires 395.7.55 (2H, d, J = 8 Hz), 7.60 (2H, d, J = 8 Hz). 48 F1-{4-[1,1-difluoro-2-oxo-2- Found 414 1.87 (8H, m), 2.72 (4H, (1- (ES+),retention m), 3.50 (2H, m), pyrrolidinyl)ethyl]phenyl}-3- time 3.61mins. 3.57 (2H, m), 7.61 (2H, d, (trifluoromethyl)-4,5,6,7- C₂₀H₂₀F₅N₃OJ = 9 Hz), 7.71 (2H, d, tetrahydro-1H-indazole requires 413. J = 8 Hz).

EXAMPLE 49N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)methanesulfonamide

The title compound was prepared from1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazoleand N-methyl methanesulfonamide using a similar procedure to thatdescribed for Description 15.

LC/Mass Spec (ES): Found 388 (ES+), retention time 3.35 mins.C₁₇H₂₀F₃N₃O₂S requires 387.

¹H-NMR (400 MHz, CDCl₃): 1.83 (4H, m), 2.70 (4H, m), 2.79 (3H, s), 2.88(3H, s), 4.36 (2H, s), 7.48 (4H, m).

EXAMPLE 501-(4-{[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]methyl}phenyl)-2-pyrrolidinone

A solution of4-{[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]methyl}aniline(166 mg, 0.56 mmol) in dichloromethane (4 ml) was treated withdiisopropylethylamine (1.12 mmol, 146 mg) followed by 4-chlorobutyrylchloride (80 mg, 0.56 mmol). After stirring at room temperature for 15minutes a solid suspension of sodium hydride (60% in mineral oil) (22mg, 0.55 mmol) was added and stirring continued for 30 minutes. Thedichloromethane was removed by blowing with air and dimethylformamideadded (3 ml) and stirring continued for 30 minutes. The reaction mix waspartitioned between dichloromethane and water (2×5 ml). The organiclayer was dried over sodium sulphate and evaporated under reducedpressure to give a yellow oil (190 mg) which was purified by massdirected auto prep to give the title compound as a yellow oil (39 mg,19%).

LC/Mass Spec (ES): Found 364 (ES+), retention time 3.13 mins.C₁₉H₂₀F₃N₃O requires 363.

¹H-NMR (400 MHz, CDCl₃): 1.65-1.81 (4H, m), 2.15 (2H, m), 2.43 (2H, m),2.62 (4H, m), 3.84 (2H, m), 5.22 (2H, s), 7.15 (2H, d, J=9 Hz), 7.57(2H, m).

EXAMPLE 51N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-1-pyrrolidinecarboxamide

A mixture of N-[(4-bromophenyl)methyl]-N-methyl-1-pyrrolidinecarboxamide(250 mg, crude), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (152mg, 0.8 mmol), N,N-dimethylglycine (20 mol %, 16.5 mg, 0.16 mmol),copper (I) iodide (10 mol %, 15 mg, 0.08 mmol) and potassium carbonate(1.6 mmol, 221 mg) in dimethylsulfoxide (4 ml) was stirred at 190° C. ina microwave reactor for 30 minutes. The reaction mix was treated withfresh N,N-dimethylglycine and copper (I) iodide and heated at 190° C. ina microwave reactor for a further 30 minutes. The reaction mix waspartitioned between dichloromethane (5 ml) and water (5 ml). The organiclayer was added to a 5 g isolute silica sep-pak column and eluted withethyl acetate. The solvent was removed under reduced pressure and theresidue purified by mass directed auto-prep (MDAP) to give the titlecompound as a brown oil (12 mg, 4%).

LC/Mass Spec (ES): Found 407 (ES+), retention time 3.50 mins.C₂₁H₂₅F₃N₄O requires 406.

¹H-NMR (400 MHz, CDCl₃): 1.85 (8H, m), 2.69 (4H, m), 2.78 (3H, s), 3.39(4H, m), 4.46 (2H, s), 7.39 (2H, d, J=9 Hz), 7.45 (2H, m).

EXAMPLE 525-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-2-pyrrolidinone

A mixture of 5-(4-bromophenyl)-2-pyrrolidinone (81 mg, 0.34 mmol;preparation described in WO00/21958),3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (64 mg, 0.34 mmol)N,N-dimethylglycine (20 mol %, 7 mg, 0.07 mmol), copper (I) iodide (10mol %, 6.5 mg, 0.034 mmol) and potassium carbonate (0.7 mmol, 97 mg) indimethylsulfoxide (2 ml) was stirred at 190° C. in a microwave reactorfor 30 minutes. The reaction mix was cooled and partitioned betweendichloromethane (5 ml) and water (5 ml). The organic layer was added toa 5 g isolute silica sep-pak column and eluted with ethyl acetate. Thesolvent was removed under reduced pressure to give a dark oil (161 mg)which was further purified by mass directed auto-prep (MDAP) to give thetitle compound as a yellow oil (17 mg, 14%).

LC/Mass Spec (ES): Found 350 (ES+), retention time 2.99 mins.C₁₈H₁₈F₃N₃O requires 349.

¹H-NMR (400 MHz, CDCl₃): 1.83 (4H, m), 1.97 (1H, m), 2.48 (2H, m), 2.52(1H, m), 2.70 (4H, m), 4.83 (1H, t, J=7 Hz), 6.13 (1H, bs), 7.40 (2H,m), 7.51 (2H, m).

EXAMPLE 53-54

The title compounds were prepared fromN-[1-(4-bromophenyl)ethyl]acetamide (Example 53) orN-[1-(4-bromophenyl)ethyl]-N-methylacetamide (Example 54) and3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similarprocedure to that used for example 51. Example R Name LC/Mass Spec (ES)53 H N-(1-{4-[3-(trifluoromethyl)- Found 352 (ES+), retention time4,5,6,7-tetrahydro-1H-indazol-1- 3.08 mins. C₁₈H₂₀F₃N₃O requires 351.yl]phenyl}ethyl)acetamide 54 Me N-methyl-N-(1-{4-[3- Found 366 (ES+),retention time (trifluoromethyl)-4,5,6,7- 3.31 mins. C₁₉H₂₂F₃N₃Orequires tetrahydro-1H-indazol-1- 365. yl]phenyl}ethyl)acetamide

EXAMPLE 55-56

The title compounds was prepared from1-acetyl-2-(4-bromophenyl)pyrrolidine (Example 55),1-[2-(4-bromophenyl)ethyl]-2-pyrrolidinone (Example 56) and3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similarprocedure to that described for Example 52. Ex- am- ple R Name LC/MassSpec (ES) 55

1-[4-(1-acetyl-2- pyrroli- dinyl)phenyl]-3- (trifluoromethyl)-4,5,6,7-tetra- hydro-1H- indazole Found 378 (ES+), retention time 3.23mins. C₂₀H₂₂F₃N₃O requires 377. 56

1-(2-{4-[3- (trifluoromethyl)- 4,5,6,7-tetra- hydro-1H- indazol-1-yl]phe- nyl}ethyl)-2- pyrrolidinone Found 378 (ES+), retention time 3.30mins. C₂₀H₂₂F₃N₃O requires 377.

EXAMPLE 571-{4-[(1,1-dioxido-2-isothiazolidinyl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

A mixture of 2-[(4-bromophenyl)methyl]isothiazolidine 1,1-dioxide (290mg, 1.0 mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (190mg, 1.0 mmol), N,N-dimethylglycine (20 mol %, 21 mg, 0.2 mmol), copper(I) iodide (10 mol %, 19 mg, 0.1 mmol) and potassium carbonate (2 mmol,276 mg) in dimethylsulfoxide (4 ml) was stirred at 190° C. in amicrowave reactor for 30 minutes. The reaction mix was partitionedbetween dichloromethane (5 ml) and water (5 ml). The organic layer wasadded to a 5 g isolute silica sep-pak column and eluted with ethylacetate. The solvent was removed under reduced pressure and the residuepurified by mass directed auto-prep (MDAP) to give a greasy productwhich was partitioned between water and dichloromethane. The organiclayer was dried over sodium sulphate and evaporated in air to give thetitle compound as a yellow oil (103 mg, 26%).

LC/Mass Spec (ES): Found 400 (ES+), retention time 3.31 mins.C₁₈H₂₀F₃N₃O₂S requires 399.

¹H-NMR (400 MHz, CDCl₃): 1.83 (4H, m), 2.34 (2H, m), 2.69 (4H, m), 3.12(2H, t, J=6 Hz), 3.23 (2H, t, J=8 Hz), 4.23 (2H, s), 7.47 (4H, m).

EXAMPLES 58-60

Typical procedure: A solution of({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)amine(description 20, 0.2 mmol) in 5% dimethylformamide in dichloromethane (2ml) was treated with triethylamine (2 equivalents, 0.05 ml) in a 15 mlsarstedt tube. The reaction mix was shaken for 20 minutes and then theappropriate acid chloride (0.05 ml) was added and the reaction mixturesshaken overnight. The reaction mixture was then quenched with water andseparated between dichloromethane and brine. The organic layer wasretained and the samples purified either on a 5 g pre-packed silicacolumn eluting from 50% ethyl acetate in petroleum ether (examples 58and 59) or by mass directed auto prep (MDAP, example 60). Relevantfractions were combined and the solvent removed by rotary evaporation togive the named products. Example R Name LC/Mass Spec (ES) 58 iPr2-methyl-N-({4-[3- Found 366 (ES+), (trifluoromethyl)-4,5,6,7- retentiontime tetrahydro-1H-indazol-1- 3.26 mins. yl]phenyl}methyl)propanamideC₁₉H₂₂F₃N₃O requires 365. 59 nPr N-({4-[3-(trifluoromethyl)-4,5,6,7-Found 366 (ES+), tetrahydro-1H-indazol-1- retention timeyl]phenyl}methyl)butanamide 3.17 mins. C₁₉H₂₂F₃N₃O requires 365. 602-thienyl N-({4-[3-(trifluoromethyl)-4,5,6,7- Found 406 (ES+),tetrahydro-1H-indazol-1- retention time yl]phenyl}methyl)-2- 3.43 mins.thiophenecarboxamide C₂₀H₁₈F₃N₃OS requires 405.

EXAMPLES 61-63

Typical procedure: The title compounds were prepared from1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole(Description 17) and propanamide (example 61), acetamide (example 62)and 2-phenylacetamide (example 63) using a similar procedure to thatdescribed for description 15. Example R R′ Name LC/Mass Spec (ES) 61 EtH N-({4-[3-(trifluoromethyl)-4,5,6,7- Found 352 (ES+),tetrahydro-1H-indazol-1- retention time yl]phenyl}methyl)propanamide3.06 mins. C₁₈H₂₀F₃N₃O requires 351. 62 Me HN-({4-[3-(trifluoromethyl)-4,5,6,7- Found 338 (ES+),tetrahydro-1H-indazol-1- retention time yl]phenyl}methyl)acetamide 2.90mins. C₁₇H₁₈F₃N₃O requires 337. 63 CH₂Ph Me N-methyl-2-phenyl-N-({4-[3-Found 428 (ES+), (trifluoromethyl)-4,5,6,7- retention timetetrahydro-1H-indazol-1- 3.60 mins. yl]phenyl}methyl)acetamideC₂₄H₂₄F₃N₃O requires 427.

EXAMPLES 64-71

Typical Procedure: A mixture of4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid(155 mg, 0.5 mmol), and 1,1′-carbonyldiimidazole (122 mg, 0.75 mmol) wasdissolved in dichloromethane (2 ml) in a 15 ml plastic tube and shakenfor 20 minutes. Then a solution of the secondary amine indichloromethane (1 ml) was added in one portion (if the amine availableas a HCl salt then triethylamine (51 mg, 0.5 mmol) was added). Thereaction mixtures were shaken for 3 hours. Reaction mixture was washedwith brine, the organic layer was retained and dried with sodiumsulphate. All samples were purified by MDAP to give the named products.Example NR1R2 Name LC/Mass Spec (ES) 64 N(Me)CH₂CH₂OHN-(2-hydroxyethyl)-N- Found 368 (ES+), methyl-4-[3- retention time(trifluoromethyl)- 2.74 mins. 4,5,6,7-tetrahydro- C₁₈H₂₀F₃N₃O₂1H-indazol-1- requires 367. yl]benzamide 65 N(Me)CH₂CH₂OMeN-methyl-N-[2- Found 382 (ES+), (methyloxy)ethyl]-4- retention time[3-(trifluoromethyl)- 3.14 mins. 4,5,6,7-tetrahydro- C₁₉H₂₂F₃N₃O₂1H-indazol-1- requires 381. yl]benzamide 66 N(Me)CH₂CH₂NHMeN-methyl-N-[2- Found 381 (ES+), (methylamino)ethyl]- retention time4-[3-(trifluoromethyl)- 2.13 mins. 4,5,6,7-tetrahydro- C₁₉H₂₃F₃N₄O1H-indazol-1- requires 380. yl]benzamide formic acid salt 671-(3-OH)pyrrolidinyl 1-({4-[3- Found 380 (ES+), (trifluoromethyl)-retention time 4,5,6,7-tetrahydro- 2.78 mins. 1H-indazol-1- C₁₉H₂₀F₃N₃O₂yl]phenyl}carbonyl)-3- requires 379. pyrrolidinol 681-(3-NHMe)pyrrolidinyl N-methyl-1-({4-[3- Found 393 (ES+),(trifluoromethyl)- retention time 4,5,6,7-tetrahydro- 1.92 mins.1H-indazol-1- C₂₀H₂₃F₃N₄O yl]phenyl}carbonyl)-3- requires 392.pyrrolidinamine formic acid salt 69 1-azetidinyl 1-[4-(1- Found 350(ES+), azetidinylcarbonyl)phenyl]- retention time 3- 3.08 mins.(trifluoromethyl)- C₁₈H₁₈F₃N₃O 4,5,6,7-tetrahydro- requires 349.1H-indazole 70 1-(3-OH)azetidinyl 1-({4-[3- Found 366 (ES+),(trifluoromethyl)- retention time 4,5,6,7-tetrahydro- 2.70 mins.1H-indazol-1- C₁₈H₁₈F₃N₃O₂ yl]phenyl}carbonyl)-3- requires 365.azetidinol 71 1-(3,3-difluoro)azetidinyl (3,3- Found 386 (ES+),difluorocyclobutyl){4- retention time [3-(trifluoromethyl)- 3.39 mins.4,5,6,7-tetrahydro- C₁₈H₁₆F₅N₃O 1H-indazol-1- requires 385.yl]phenyl}methanone

EXAMPLE 721-[4-(1H-imidazol-1-yl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

A mixture of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (152 mg,0.8 mmol), potassium carbonate (232 mg, 1.68 mmol) and copper (I) iodide(1 mg, 0.005 mmol) was treated with a solution oftrans-1,2-diaminocyclohexane (9 mg, 0.08 mmol) in dioxane followed by asolution of 1-(4-bromophenyl)imidazole (161 mg, 0.72 mmol) in dioxane (4ml total volume). This mixture was heated at 180° C. in a microwavereactor for 1 hour. Further copper (I) iodide (1 mg) andtrans-1,2-diaminocyclohexane (9 mg) was added and the reaction heated at180° C. in a microwave reactor for a further hour. Again further copper(I) iodide (1 mg) and trans-1,2-diaminocyclohexane (9 mg) was added andthe reaction heated at 180° C. in a microwave reactor for a furtherhour. The reaction mixture was added to a 5 g sep-pack column and elutedwith ethyl acetate. The solvent was removed by rotary evaporation andthe crude product further purified by MDAP. Further purified using a 5 gSCX column, eluting from 1M ammonia in methanol which was thenevaporated off using rotary evaporation to give the title compound (42mg, 18%).

LC/Mass Spec (ES): Found 333 (ES+), retention time 2.21 mins. C₁₇H₁₅F₃N₄requires 332.

¹H-NMR (400 MHz, CDCl₃): 1.85 (4H, m), 2.73 (4H, m), 7.25 (1H, m), 7.32(1H, m), 7.51 (2H, m), 7.63 (2H, m), 7.89 (1H, s).

EXAMPLES 73-74

A solution of({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)amine(436 mg, 1.48 mmol) in 10% dimethylformamide in dichloromethane (5 ml)was treated with triethylamine (2.96 mmol, 0.41 ml). The reaction mixwas stirred for 5 minutes and then 2-propenoyl chloride (0.13 ml) wasadded dropwise and the reaction mixture stirred for a further 1.5 hours.The reaction mixture was then quenched with water and separated betweendichloromethane and brine. The organic layer was retained and dried oversodium sulphate. The solvent was removed by rotary evaporation and thesample purified on a biotage 25+M column with 0-100% ethylacetate/n-pentane solvent gradient. Combining relevant fractions andremoving solvent by rotary evaporation gave the named products. LC/MassSpec 1H-NMR Ex R Name (ES) (250 MHz, CDCl₃) 73 H N-({4-[3-(trifluoromethyl)- 4,5,6,7-tetrahydro- 1H-indazol-1-yl]phenyl}methyl)-2- propenamide Found 350 (ES+), retention time 3.06mins. C₁₈H₁₈F₃N₃O requires 349. 1.81 (4 H, m), 2.665 (4 H, m), 4.52 (2H, d, J = 6 Hz), 5.67 (1 H, #dd, J = 10 Hz & 2 Hz), 6.07- 6.20 (1 H, m),6.33 (1 H, m), 6.46 (1 H, m), 7.37 (4 H, m). 74

N-(1-methylethenyl)- N-({4-[3- (trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indazol-1- yl]phenyl}methyl)-2- propenamide Found 390 (ES+),retention time 3.61 mins. C₂₁H₂₂F₃N₃O requires 389. 1.81 (4 H, m), 1.89(3 H, s), 2.68 (4 H, m), #4.69 (1 H, s), 4.77 (2 H, s), 5.05 (1 H, d, J= 2 Hz), 5.68 (1 H, dd, J = 10 Hz & 2 Hz), 6.44 (1 H, m), 6.55-6.66 (1H, m), 7.41 (4 H, s).

EXAMPLE 75N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propenamide

A stirred solution ofN-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propenamide(241 mg, 0.69 mmol) in dimethylformamide (5 ml) under argon was treatedwith sodium hydride (60% suspension in mineral oil, 28 mg, 0.7 mmol).The reaction mixture was stirred for 5 minutes then methyl iodide (0.05ml) was added and the reaction mixture stirred for a further 1 hour.Reaction mixture was then quenched with 3 drops of water and 5 ml of 1Mammonia in methanol. Excess ammonia and methanol were removed by rotaryevaporation. Reaction mixture was separated between ethyl acetate andbrine. Organic layer was retained, dried over sodium sulphate and thesolvent removed by rotary evaporation. Sample was purified by 5 gpre-pack silica column eluted with 50% ethyl acetate/petroleum ether.Relevant fractions were combined and the solvent removed by rotaryevaporation to give the title compound as a yellow oil (66 mg, 26%).

LC/Mass Spec (ES): Found 364 (ES+), retention time 3.26 mins.C₁₉H₂₀F₃N₃O requires 363.

¹H-NMR (250 MHz, CDCl₃): 1.82 (4H, bs), 2.68 (4H, bs), 3.02 (3H, m),4.68 (2H, m), 5.68-5.80 (1H, m), 6.36-4.46 (1H, m), 6.52-6.71 (1H, m),7.27-7.51 (4H, m).

EXAMPLES 76-77

Typical procedure: A mixture of{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}aceticacid (90 mg, 0.28 mmol), and 1-hydroxybenzotriazole (45 mg, 0.33 mmol)were slurried in dry acetonitrile.1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (61mg, 0.32 mmol) was added in one portion and the reaction mixture stirredfor 30 minutes at room temperature. The appropriate amidoxime was addedin one portion and the reaction heated under reflux for 4 hours in thepresence of 4 A molecular sieves. A further 0.5 equivalents of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was addedand the reflux continued for 4-6 hours. Reaction mixtures wereevaporated to dry residue and separated between ethyl acetate andsaturated aqueous sodium bicarbonate solution. The organic layer wasretained and the solvent removed by rotary evaporation and the samplepurified by MDAP. Relevant fractions were combined and the solventremoved by rotary evaporation to give the named products. LC/Mass Spec1H-NMR Example R Name (ES) (250 MHz, CDCl₃) 76 Me 1-{4-[(3-methyl-1,2,4-Found 363 (ES+), 1.83 (4H, m), 2.39 (3H, oxadiazol-5- retention time s),2.69 (4H, m), yl)methyl]phenyl}-3- 3.45 mins. 4.24 (2H, s), 7.43 (2H,m), (trifluoromethyl)- C₁₈H₁₇F₃N₄O 7.48 (2H, m). 4,5,6,7-tetrahydro-1H-requires 362. indazole 77 cPr 1-{4-[(3-cyclopropyl- Found 389 (ES+),1.04 (4H, m), 1.82 (4H, 1,2,4-oxadiazol-5- retention time m), 2.07 (1H,m), yl)methyl]phenyl}-3- 3.69 mins. 2.69 (4H, m), 4.20 (2H, s),(trifluoromethyl)- C₂₀H₁₉F₃N₃O 7.41 (2H, m), 7.47 (2H,4,5,6,7-tetrahydro-1H- requires 388. m). indazole

EXAMPLE 78N-ethyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide

A suspension of4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid(310 mg, 1.0 mmol) in dichloromethane (5 ml) was treated with1,1′-carbonyldiimidazole (162 mg, 1.0 mmol) at room temperature underargon. This mix was stirred for 30 minutes and then treated with a 2Msolution of ethylamine in tetrahydrofuran (0.5 ml). The whole mix wasstirred at room temperature for 2 hours. The reaction mixture was washedwith saturated aqueous sodium bicarbonate. The organic layer wasseparated, dried over sodium sulphate and reduced to minimum volume byrotary evaporation to give a beige solid (250 mg) which was purified bycolumn chromatography on a 5 g pre-packed silica column, eluting from0-50% ethyl acetate in petroleum ether to give the title compound as acolourless solid (128 mg, 38%).

LC/Mass Spec (ES): Found 338 (ES+), retention time 3.13 mins.C₁₇H₁₈F₃N₃O requires 337.

¹H-NMR (400 MHz, CDCl₃): 1.28 (3H, t, J=7 Hz), 1.83 (4H, m), 2.68 (2H,bs), 2.74 (2H, bs), 3.53 (2H, m), 6.15 (1H, bs), 7.59 (2H, m), 7.89 (2H,m).

EXAMPLE 79-81

A solution of4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid(MWt=310) in dichloromethane (2 ml) was treated with1,1′-carbonyldiimidazole (1 equivalent, MWt=162) in one portion andstirred at room temperature for 15 minutes. Then the secondary amine(1.15 equivalents) was added and stirring continued for 1 hour. Thereaction mix was added to a 5 g pre-packed silica column and eluted with0-50% ethyl acetate in 40-60° C. petroleum ether. The product wasoptionally purified further by MDAP to give the named compounds. ExampleNR1R2 Name LC/Mass Spec (ES) 79 N(Me)iPr N-methyl-N-(1- Found 366 (ES+),methylethyl)-4-[3- retention time (trifluoromethyl)-4,5,6,7- 3.47 mins.tetrahydro-1H-indazol-1- C₁₉H₂₂F₃N₃O requires yl]benzamide 365. 801-piperidinyl 1-[4-(1- Found 378 (ES+), piperidinylcarbonyl)phenyl]-retention time 3-(trifluoromethyl)- 3.54 mins.4,5,6,7-tetrahydro-1H-indazole C₂₀H₂₂F₃N₃O requires 377. 81 NEt₂N,N-diethyl-4-[3- Found 366 (ES+), (trifluoromethyl)-4,5,6,7- retentiontime tetrahydro-1H-indazol-1- 3.48 mins. yl]benzamide C₁₉H₂₂F₃N₃Orequires 365.

EXAMPLE 82N-methyl-4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzamide

A solution of4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid(87 mg, 0.28 mmol) and diisopropylethylamine (0.1 ml) in dichloromethane(3 ml) was treated with 1,1′-carbonyldiimidazole (46 mg, 0.28 mmol) inone portion and stirred at room temperature for 15 minutes. Thenmethylamine hydrochloride (22 mg, 0.33 mmol) was added and stirringcontinued for 1 hour. The reaction mix was added to a 5 g pre-packedsilica column and eluted with 0-50% ethyl acetate in petroleum ether togive the title compound (28 mg, 31%).

LC/Mass Spec (ES): Found 324 (ES+), retention time 3.04 mins.C₁₆H₁₆F₃N₃O requires 323.

¹H-NMR (400 MHz, CDCl₃): 1.83 (4H, m), 2.68 (2H, bs), 2.75 (2H, bs),3.05 (3H, d, J=5 Hz), 6.17 (1H, m), 7.59 (2H, m), 7.87 (2H, m).

EXAMPLE 831-{4-[2-oxo-2-(2-phenyl-1-pyrrolidinyl)ethyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

A solution of{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}aceticacid (65 mg, 0.2 mmol) in dichloromethane (2 ml) was treated with1,1′-carbonyldiimidazole (32.5 mg, 0.2 mmol) in one portion at roomtemperature. Stirring was continued at room temperature for 15 minutes.Then 2-phenylpyrrolidine (29 mg, 0.2 mmol) was added and stirringcontinued for 1 hour. Most of the solvent was removed under reducedpressure and the crude product was further purified by MDAP to give thetitle compound (55 mg, 61%).

LC/Mass Spec (ES): Found 454 (ES+), retention time 3.61 mins.C₂₆H₂₆F₃N₃O requires 453.

EXAMPLE 84N-methyl-N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)benzamide

A solution of{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanol(286 mg, 0.97 mmol) was dissolved in dichloromethane (5 ml) and stirredunder an atmosphere of argon in a methanol/ice bath. Triethylamine (106mg, 1.05 mmol, 0.15 ml) was added in one portion and the reactionmixture stirred for a further 15 minutes. Methanesulfonyl chloride (115mg, 1 mmol, 0.08 ml) was added dropwise over 10 minutes. The reactionmixture was stirred for a further 10 minutes at below 0° C., thenallowed to return to room temperature. The reaction mixture was thenseparated between dichloromethane (5 ml) and water (30 ml). the organiclayer was retained, dried using sodium sulphate and the solvent removedby rotary evaporation to give the crude mesylate (A) (299 mg).

N-methylbenzamide (20 mg, 0.14 mmol) was dissolved in dimethylformamide(1 ml) and shaken in a 15 ml plastic sarstedt tube. Sodium hydride (60%suspension in mineral oil, 6 mg, 0.15 mmol) was added in one portion andthe reaction was shaken for 15 minutes. A solution of the mesylate (A)(50 mg, 0.13 mmol) in dimethylformamide (1 ml) was added dropwise over10 minutes. The reaction mixture was shaken for a further 30 minutes.The reaction vessel was then flushed with argon and shaken for 3 days.The reaction mixture was separated between dichloromethane (30 ml) andwater (20 ml) with brine (10 ml). The dichloromethane layer was washedwith water (2×20 ml) and dried with sodium sulphate. Solvent was removedby rotary evaporation and the sample purified by MDAP. Relevany fractionwere combined and the solvent removed by rotary evaporation to give thetitle compound (4 mg, 7%).

LC/Mass Spec (ES): Found 414 (ES+), retention time 3.57 mins.C₂₃H₂₂F₃N₃O requires 413.

¹H-NMR (400 MHz, CDCl₃): 1.83 (4H, m), 2.70 (4H, m), 2.89 & 3.06 (3H, m,rotomers), 4.57 & 4.81 (2H, m, rotomers), 7.35-7.52 (9H, m).

EXAMPLE 851-[4-(1,3-oxazol-5-yl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

A mixture of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (152 mg,0.8 mmol), 5-(4-bromophenyl)-1,3-oxazole (179 mg, 0.8 mmol),N,N-dimethylglycine (16 mg, 0.16 mmol), copper (I) iodide (16 mg, 0.08mmol), potassium carbonate (235 mg, 1.7 mmol) in dimethylsulfoxide (3ml) was heated in a microwave reactor at 180° C. for a total of 60minutes. The reaction mixture was then filtered through a 5 g sep-packcolumn with 40 ml 1:1 ethyl acetate in petroleum ether. The solvent wasremoved by rotary evaporation and the residue partitioned between ethylacetate (20 ml) and water (20 ml). The organic layer was retained andwashed with brine (2×10 ml). The organic material was then purified byMDAP. The relevant fractions were combined and the solvent removed byrotary evaporation to give the named products. Product was thenpartitioned between dichloromethane (40 ml) and water (40 ml). Theorganic layer was retained and the solvent removed by rotary evaporationto give the title compound (80 mg, 30%).

LC/Mass Spec (ES): Found 334 (ES+), retention time 3.57 mins.C₁₇H₁₄F₃N₃O requires 333.

¹H-NMR (400 MHz, CDCl₃): 1.83 (4H, m), 2.69 (2H, bs), 2.74 (2H, bs),7.42 (1H, s), 7.58 (2H, m), 7.76 (2H, m), 7.96 (1H, m).

EXAMPLE 861-[4-(propyloxy)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

A mixture of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (152 mg,0.8 mmol), 1-bromo-4-(propyloxy)benzene (177 mg, 0.8 mmol),N,N-dimethylglycine (16 mg, 0.16 mmol), copper (I) iodide (16 mg, 0.08mmol), potassium carbonate (235 mg, 1.7 mmol) in dimethylsulfoxide (3ml) was heated in a microwave reactor at 180° C. for a total of 50minutes. Fresh N,N-dimethylglycine (16 mg, 0.16 mmol) and copper (I)iodide (16 mg, 0.08 mmol) was added and heating continued at 180° C. fora further 30 minutes. The reaction mixture was then filtered through a 5g sep-pack column with 40 ml 1:1 ethyl acetate in petroleum ether. Thesolvent was removed by rotary evaporation and the residue partitionedbetween ethyl acetate (20 ml) and water (20 ml). The organic layer wasretained and washed with brine (2×10 ml), then dried over sodiumsulphate. The solvent was removed by rotary evaporation and the samplepurified by MDAP. The relevant fractions were combined and the solventremoved by rotary evaporation to give the title compound (23 mg, 9%).

LC/Mass Spec (ES): Found 325 (ES+), retention time 4.01 mins.C₁₇H₁₉F₃N₂O requires 324.

¹H-NMR (400 MHz, CDCl₃): 1.05 (3H, t, J=8 Hz), 1.83 (6H, m), 2.65 (4H,m), 3.95 (2H, t, J=7 Hz), 6.96 (2H, m), 7.36 (2H, m).

EXAMPLE 871-[4-(1-methyl-1H-imidazol-4-yl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

A mixture of copper (I) iodide (10 mol %, 5 mg, 0.02 mmol),3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (50 mg, 0.26 mmol),potassium carbonate (73 mg, 0.52 mmol) in DMSO (2 ml) was stirred for 1min, then 4-(4-bromophenyl)-1-methyl-1H-imidazole (62 mg, 0.26 mmol)(WO91/09855) and N,N-dimethylglycine (20 mol %, 5.4 mg) were thensuccessively added. The reaction tube was quickly sealed and thecontents were heated in a microwave reactor at 180° C. for 40 mins. Thereaction mixture was partitioned between ethyl acetate and water, driedwith sodium sulphate and solvent was removed by rotary evaporation andthe sample purified by MDAP. The solvent was removed by rotaryevaporation to give the title compound as a solid (15 mg, 16%).

LC/Mass Spec (ES): Found 347 (ES+), retention time 2.23 mins. C18H17F3N4requires 346.

¹H-NMR (400 MHz, CDCl3): 1.82 (4H, m), 2.70 (4H, m), 3.75 (3H, s), 7.23(1H, m), 7.48 (3H, d, J=8.8 Hz), 7.83 (2H, d, J=8.4 Hz).

EXAMPLE 88N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)-2-propanesulfonamide

A mixture of({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)amine(100 mg, 0.339 mmol), triethylamine (0.07 ml, 0.51 mmol) in DCM (10 ml)was stirred in an ice bath under argon. Then isopropylsulfonyl chloridewas added (148 mg in total, 1 mmol) in DCM (1 ml) dropwise withstirring. The reaction mixture was allowed to stir at room temperaturefor 16 hr. Then the reaction mixture was washed with water (20 ml),separated the organic layer and dried with sodium sulphate. Solvent wasremoved by rotary evaporation and the sample purified by MDAP to givethe title compound as an off white solid (51 mg, 37%).

LC/Mass Spec (ES): Found 402 (ES+), retention time 3.40 mins.C18H22F3N3O2S requires 401.

¹H-NMR (400 MHz, CDCl3): 1.4 (6H, d, J=6.8 Hz), 1.8 (4H, m), 2.68 (4H,m), 3.12 (1H, m), 4.36 (3H, m), 7.47 (4H, m).

EXAMPLE 89N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)cyclopropanesulfonamide

The title compound was prepared from({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)amineand cyclopropanesulphonyl chloride using a similar procedure to thatdescribed for Example 88.

LC/Mass Spec (ES): Found 400 (ES+), retention time 3.35 mins.C₁₈H₂₀F3N3O2S requires 399.

¹H-NMR (400 MHz, CDCl3): 0.9 (2H, m), 1.17 (2H, m), 1.80 (4H, m), 2.37(1H, m), 2.70 (4H, m), 4.40 (2H, d, J=6 Hz), 4.62 (1H, m), 7.43-7.54(4H, m).

EXAMPLE 90N-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)cyclopentanesulfonamide

The title compound was prepared from({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)amineand cyclopentanesulphonyl chloride using a similar procedure to thatdescribed for Example 88.

LC/Mass Spec (ES): Found 428 (ES+), retention time 3.41 mins.C20H24F3N3O2S requires 427.

¹H-NMR (400 MHz, CDCl3): 1.62 (2H, m), 1.80 (6H, m), 2.0 (4H, m), 2.68(4H, m), 3.40 (1H, m), 4.38 (2H, m), 4.46 (1H, m), 7.42-7.52 (4H, m).

EXAMPLE 911-[4-(1-pyrrolidinylsulfonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

The title compound was prepared from1-[(4-iodophenyl)sulfonyl]pyrrolidine and3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similarprocedure to that described for Example 87.

LC/Mass Spec (ES): Found 400 (ES+), retention time 3.59 mins.C18H20F3N3O2S requires 399.

¹H-NMR (400 MHz, CDCl3): 1.77 (4H, m), 1.84 (4H, m), 2.67 (2H, m), 2.76(2H, m), 3.27 (4H, m), 7.69 (2H, m), 7.94 (2H, m).

EXAMPLES 92-96

Typical Procedure: A mixture of copper (I) iodide (20 mol %, 20 mg),3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (100 mg, 0.53 mmol),potassium carbonate (146 mg, 1.05 mmol) in DMSO (2 ml). The mixture wasstirred for 1 min, then the 4-iodobenzenesulfonamide derivative (0.53mmol) and N,N-dimethylglycine (20 mol %, 10 mg) were successively added.The reaction tube was quickly sealed and the contents were heated in amicrowave reactor at 180° C. for 40 mins. The reaction mixture waspartitioned between ethyl acetate and water, dried with sodium sulphateand solvent was removed by rotary evaporation and the sample purified byMDAP. The solvent was removed by rotary evaporation to give the namedproducts. Example NR1R2 Name LC/Mass Spec (ES) 92

N-(2-methylpropyl)-4-[3- (trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1- yl]benzenesulfonamide Found 402 (ES+),retention time 3.67 mins. C18H22F3N3O2S requires 401. 93

1-[4-(4- morpholinylsulfonyl)phenyl]- 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole Found 416 (ES+), retention time 3.35 mins.C18H20F3N3O3S requires 415. 94

N-[2-(methyloxy)ethyl]-4- [3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1- yl]benzenesulfonamide Found 404 (ES+),retention time 3.30 mins. C17H20F3N3O3S requires 403. 95

N-[2-(1-pyrrolidinyl)ethyl]- 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H- indazol-1- yl]benzenesulfonamide Found 443 (ES+),retention time 2.29 mins. C20H25F3N4O2S requires 442. 96

N-(tetrahydro-2- furanylmethyl)-4-[3- (trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1- yl]benzenesulfonamide Found 430 (ES+),retention time 3.39 mins. C19H22F3N3O3S requires 429.

EXAMPLE 971-[4-(1H-imidazol-1-ylmethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

Sodium hydride (60% in mineral oil, 14.0 mg; 0.35 mmol) was added in oneportion to a room temperature stirring solution of imidazole (11.5 mg;0.17 mmol) in anhydrous DMF (1 mL). After stirring at this temperaturefor 1 hour, a solution of1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole(61.2 mg; 0.19 mmol) in anhydrous DMF (0.4 mL) was added in one portionand the resulting mixture stirred at room temperature for a further 16hours. The reaction was quenched with aqueous hydrochloric acid (0.2 M;0.2 mL), and purified by SCX column chromatography, giving the titlecompound as a yellow oil (51.8 mg; 89%).

LC/Mass Spec (ES): Found 347 (ES+), retention time 2.18 mins. C₁₈H₁₇F₃N₄requires 346.

¹H-NMR (400 MHz, CDCl₃): 1.77-1.95 (4H, m), 2.60-2.74 (4H, m), 5.18 (2H,s), 6.90-6.93 (1H, m), 7.12 (1H, app s), 7.22-7.29 (2H, m), 7.47-7.52(2H, m), 7.56 (1H, app s).

EXAMPLES 98-99

The named examples were prepared from1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazoleand the appropriate azole heterocycle in a manner similar to thatdescribed for example 97.

Ex Het Name LC/Mass Spec (ES) 98

1-[4-(1H-1,2,4-triazol-1- ylmethyl)phenyl]-3- (trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole Found 348 (ES+), retention time 3.05 mins.C₁₇H₁₆F₃N₅requires 347. 99

1-[4-(1H-pyrazol-1- ylmethyl)phenyl]-3- (trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole Found 347 (ES+), retention time 3.36 mins.C₁₈H₁₇F₃N₄requires 346.

EXAMPLE 1021-{4-[(4-methyl-1H-pyrazol-1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole

Sodium hydride (60% in mineral oil, 10.0 mg; 0.25 mmol) was added in oneportion to a room temperature stirring solution of 4-methyl-1H-pyrazole(15.0 mg; 0.18 mmol) in anhydrous DMF (1 mL). After stirring at thistemperature for 15 minutes, a solution of1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole(52.0 mg; 0.16 mmol) in anhydrous DMF (1 mL) was added and the resultingmixture stirred at room temperature for a further 23 hours. The reactionwas quenched with aqueous hydrochloric acid (2M; 1 mL), concentrated invacuo and purified by MDAP, giving the title compound (35.6 mg; 60%).

LC/Mass Spec (ES): Found 361 (ES+), retention time 3.42 mins. C₁₉H₁₉F₃N₄requires 360.

¹H-NMR (400 MHz, CDCl₃): 1.76-1.89 (4H, m), 2.08 (3H, s), 2.61-2.74 (4H,m), 5.29 (2H, s), 7.16 (1H, s), 7.23-7.31 (2H, m), 7.36 (1H, s),7.42-7.48 (2H, m).

EXAMPLES 103-111

The named examples were prepared from1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazoleand the appropriate azole heterocycle in a manner similar to thatdescribed for example 102.

Ex Het Name LC/Mass Spec (ES) 103

1-{4-[(3,5-dimethyl-1H-pyrazol- 1-yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indazole Found 375 (ES+),retention time 3.53 mins. C₂₀H₂₁F₃N₄requires 374 104

3-(trifluoromethyl)-1-(4-{[3- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)-4,5,6,7- tetrahydro-1H-indazole Found 415 (ES+),retention time 3.75 mins. C₁₉H₁₆F₆N₄requires 414 105

3-(trifluoromethyl)-1-(4-{[5- (trifluoromethyl)-1H-pyrazol-1-yl]methyl}phenyl)-4,5,6,7- tetrahydro-1H-indazole Found 415 (ES+),retention time 3.84 mins. C₁₉H₁₆F₆N₄requires 414 106

1-(4-{[5-methyl-3- (trifluoromethyl)-1H-pyrazol-1- yl[methyl}phenyl)-3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indazole Found 429 (ES+),retention time 3.85 mins. C₂₀H₁₈F₆N₄requires 428 107

1-(4-{[3-methyl-5- (trifluoromethyl)-1H-pyrazol-1- yl[methyl}phenyl)-3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indazole Found 429 (ES+),retention time 3.94 mins. C₂₀H₁₈F₆N₄requires 428 108

1-{4-[(2-methyl-1H-imidazol-1- yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indazole Formic acid salt Found361 (ES+), retention time 1.98 mins. C₁₉H₁₉F₃N₄requires 360 109

1-(4-{[2-(1-methylethyl)-1H- imidazol-1-yl[methyl}phenyl)-3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indazole Formic acid salt Found389 (ES+), retention time 2.28 mins. C₂₁H₂₃F₃N₄requires 388 110

1-{4-[(4-phenyl-1H-imidazol-1- yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indazole Formic acid salt Found423 (ES+), retention time 2.69 mins. C₂₄H₂₁F₃N₄requires 422 111

1-{4-[(4-bromo-1H-pyrazol-1- yl)methyl]phenyl}-3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indazole Found 425 (⁷⁹Br), 427(⁸¹Br) (ES+), retention time 3.70 mins. C₁₈H₁₆ ⁷⁹BrF₃N₄requires 424,C₁₈H₁₆ ⁸¹BrF₃N₄requires 426,

EXAMPLES 100-101

Sodium hydride (60% in mineral oil, 11.0 mg; 0.28 mmol) was added in oneportion to a room temperature stirring solution of 1,2,3-triazole (11.3mg; 0.16 mmol) in anhydrous DMF (1 mL). After stirring at thistemperature for 1 hour, a solution of1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole(61.2 mg; 0.19 mmol) in anhydrous DMF (0.4 mL) was added in one portionand the resulting mixture stirred at room temperature for a further 16hours. The reaction was quenched with aqueous hydrochloric acid (0.2 M;0.2 mL), and filtered through an SCX column. The filtrate was purifiedby MDAP, giving example 101 (11.7 mg; 21%). The SCX column was flushedwith methanolic ammonia as part of the capture release SCX columnchromatography, giving example 100 (9.1 mg; 16%); Ex- am- ¹H-NMR pleName LC/Mass Spec (ES) (400 MHz, CDCl₃) 100 1-[4-(1 H-1,2,3- LC/MassSpec (ES): 1.75-1.89 (4 H, m), triazol-1- found 348 (ES+), 2.62-2.74 (4H, m), ylmethyl)phenyl]-3- retention time 3.15 5.63 (2 H, s), 7.49-(trifluoromethyl)- mins. C₁₇H₁₆F₃N₅ 7.54 (2 H, m), 7.514,5,6,7-tetrahydro- requires 347. (1 H, d (obscured), 1 H-indazole 7.75(1 H, d, J = 1 Hz) 101 1-[4-(2 H-1,2,3- found 348 (ES+), 1.75-1.87 (4 H,m), triazol-2- retention time 3.38 2.61-2.73 (4 H, m),ylmethyl)phenyl]-3- mins. C₁₇H₁₆F₃N₅ 5.66 (2 H, s), 7.37-(trifluoromethyl)- requires 347. 7.42 (2 H, m), 7.44-4,5,6,7-tetrahydro- 7.49 (2 H, m), 7.65 1 H-indazole (2 H, s);

EXAMPLE 112(1-methyl-1H-imidazol-2-yl){4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanoneFormic Acid Salt

A stirring mixture of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole(200 mg; 1.05 mmol), 4-bromoiodobenzene (297 mg; 1.05 mmol), K₂CO₃ (302mg; 2.18 mmol), CuI (20 mg; 0.11 mmol) and N,N-dimethyl glycine (30 mg;0.29 mmol) in DMSO (4 mL) was heated at 130° C. for 5 hours 30 minutes.The reaction mixture was partitioned between DCM and water, the organicphase filtered through silica (eluent—methanol), and concentrated invacuo, giving a brown oil (411 mg). This was purified by columnchromatography, giving a mixture of1-(4-bromophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole and1-(4-iodophenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (205mg). Under an inert atmosphere of argon, 95 mg of this mixture wasdissolved in anhydrous THF (2 mL), cooled to −78° C., and n-butyllithium (2.5 M in hexanes, 330 μL; 0.82 mmol) was added dropwise over 2minutes. After stirring for 1 hour,N,1-dimethyl-N-(methyloxy)-1H-imidazole-2-carboxamide (93 mg; 0.55 mmol)was added in one portion to the cold (−78° C.) mixture and the reactionstirred at this temperature for a further 40 minutes. The reaction waswarmed to 0° C. and stirred at this temperature for 5 hours 20 minutes.Additional N,1-dimethyl-N-(methyloxy)-1H-imidazole-2-carboxamide (58 mg;0.34 mmol) was added in one portion, and the reaction stirred at 0° C.for a further 1 hour. The reaction was quenched with aqueoushydrochloric acid (1M, 2 mL), and purified by SCX column chromatography,yielding a white solid (32 mg). This was further purified by MDAP,giving the title compound as white solid (1.14 mg; 0.29% [2 steps]).

LC/Mass Spec (ES): found 375 (ES+), retention time 3.44 mins.C₁₉H₁₇F₃N₄O requires 374.

¹H-NMR (400 MHz, CD₃OD): 1.80-1.92 (4H, m), 2.68 (2H, br app s), 2.85(2H, br app s), 7.20 (1H, d, J=1 Hz), 7.45 (1H, app s), 7.70-7.75 (2H,m), 8.28-8.35 (2H, m).

EXAMPLE 113N-methyl-N-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-1-pyrrolidinecarboxamide

Under an inert atmosphere (Ar), NaH (60% in mineral oil, 3.8 mg; 95μmol) was added in one portion to a stirring solution ofN-{4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}-1-pyrrolidinecarboxamide(17.7 mg; 44 μmol) in anhydrous DMF (1.5 mL). After stirring at roomtemperature for 1 hour, MeI (20 μL; 0.32 mmol) was added in one portion,and the reaction stirred at this temperature for 2 hours 10 minutes. Thereaction was quenched with methanolic ammonia (1M, 1 mL), concentratedin vacuo and purified by column chromatography, giving the desiredmaterial as a yellow oil (15.4 mg; 84%).

LC/Mass Spec (ES): found 393 (ES+), retention time 3.46 mins.C₂₀H₂₃F₃N₄O requires 392.

¹H-NMR (400 MHz, CDCl₃): 1.67-1.77 (4H, m), 1.77-1.88 (4H, m), 2.62-2.76(4H, m), 3.04-3.18 (4H, m), 3.26 (3H, s), 7.15-7.23 (2H, m), 7.3

Example 36 requires use of [3-(1H-imidazol-1-yl)propyl]methylamine—Naiduet. al. Bioorganic & Medicinal Chemistry Letters (2004), 14(22),5573-5577.

Example 38 requires use ofN-methyl-2-(1H-1,2,4-triazol-1-yl)ethanamine—WO2004/014300.

Example 40 requires use ofN-methyl-1-(1-methyl-1H-pyrrol-2-yl)methanamine—Raines et. al. Journalof Heterocyclic Chemistry 7(1), 223-5; 1970.

Biological Assays

The ability of the compounds of the invention to potentiate glutamatereceptor-mediated response may be determined a) by using fluorescentcalcium-indicator dyes such as FLUO4 and additionally b) by measuringglutamate-evoked current recorded from human GluR2 flip unedited HEK293cells.

a) Calcium Influx Fluorescence Assay

384 well plates are prepared containing confluent monolayer of HEK 293cells either stably expressing or transiently transfected with humanGluR2 flip (unedited) AMPA receptor subunit. These cells form functionalhomotetrameric AMPA receptors. The tissue culture medium in the wellsare discarded and the wells are each washed three times with standardbuffer (80 μL) for the stable cell line (145 mM NaCl, 5 mM KCl, 1 mMMgCl₂, 2 mM CaCl₂, 20 mMN-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 5.5 mMglucose, pH 7.3) or with a Na-free buffer for the transient transfectedcells (145 mM N-methyl-glucamine instead of NaCl). The plates are thenincubated for 60 minutes in the dark with 2 μM FLUO4-AM dye (20 μL)(Molecular Probes, Netherlands) at room temperature to allow cell uptakeof the FLUO-4AM, which is then converted to FLUO-4 by intracellularesterases which is unable to leave the cell. After incubation each wellis washed three times with buffer (80 μL) (30 μL of buffer remained ineach well after washing).

Compounds of the invention (or reference compounds such ascyclothiazide) are dissolved in dimethylsulfoxide (DMSO) at a stockconcentration of 10 mM. These solutions are further diluted with DMSOusing a Biomek FX (Beckman Coulter) in a 384 compound plate. Eachdilution (1 μL) is transferred to another compound plate and buffer (50μL) is added. An agonist stimulus (glutamate) plate is prepared bydissolving sodium glutamate in water to give a concentration of 100 mM.This solution is diluted with buffer to give a final concentration of500 μM and dispensed into another 384-well plate (50 μL/well) using aMultidrop (Thermolabsystems).

The cell plate is then transferred into a fluorescence imaging platebased reader [such as the FLIPR384 (Molecular Devices)]. A baselinefluorescence reading is taken over a 10 to 240 second period, and then10 μL from each plate containing a compound of the invention made up instandard buffer solution (in a concentration range from 100 μM to 10 pM)is added (to give a final concentration in the range 30 μM to 3 pM). Thefluorescence is read over 5 minute period. 500 μM glutamate solution (10μL) is added (to give a final concentration of 100 μM). Thefluoresecence is then read over a 4 minute period. The activities of thecompounds of the invention and reference compounds are determined bymeasuring peak fluorescence after the last addition. The activity isalso expressed relative to the fluorescence increase induced bycyclothiazide at their maximum response (i.e. greater than 30 μM).

The assay described above is believed to have an effective limit ofdetection of a pEC₅₀ in the region of 3.5-4.0 due to the limitations ofcompound solubility. The pEC₅₀ result is generally considered to beaccurate +/−0.3. Accordingly, a compound exhibiting a pEC₅₀ value withinthis range from such an assay may indeed have a reasonable affinity forthe receptor, but equally it may also have a lower affinity, including aconsiderably lower affinity. For each compound, more than one readingwas taken.

All the Example compounds were screened using the assay as describedabove and the average of the measurable pEC50s were taken. All compoundsgave an average pEC₅₀ equal to or greater than 3.5 and demonstrated anactivity of, on average at least 20% that of cyclothiazide (at itsmaximal response).

b) Whole Cell Voltage-Clamp Electrophysiology Assay

The ability of the compounds of the invention to potentiate AMPA-subtypeglutamate receptor-mediated response are determined by measuringAMPA-evoked current recorded from rat cultured hippocampal neurons.

This assay involves the electrophysiological characterisation of AMPAreceptor positive modulators using rat cultured hippocampal neurons. Theextracellular recording solution contains: 145 mM NaCl, 2.5 mM KCl, 1.2mM MgCl₂, 1.5 mM CaCl₂, 10 mMN-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 10 mMD-glucose, pH 7.3 with NaOH. The intracellular solution contains: 80 mMCsCl, 80 mM CsF, 10 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonicacid (HEPES), 10 mM ethyleneglycol-bis(g-aminoethylether)-N,N,N′,N,-tetra-acetic acid (EGTA), 14 mMMgATP, 14 mM DiTris Creatine Phosphate, 50 U/ml Creatine PhosphokinasepH 7.3 with CsOH. Recording electrodes are prepared from glass capillarytubes (Clark Electromedical GC120-F10) pulled into two equal lengthsusing a Zeitz Instruments DMZ Universal Puller, program 09, resulting inelectrodes with a resistance of approximately 3-6 MOhms when measured inextracellular solution. Electrodes are back filled with internalrecording solution. Positive pressure is applied to the electrode toprevent mixture of internal and external solutions and assist information of high resistance seal when the electrode makes contact withthe cell membrane. Glass coverslip fragment, bearing rat culturedhippocampal neurons, is placed in the recording chamber positioned onthe stage of an inverted microscope. A tube at the edge of the chamberis used to apply extracellular solution to the bath. Rapid solutionexchange uses a fast step perfusion system (Biologic RSC160). Two outlettubes attached together along their length are positioned close to achosen cell so that the outflow from only one tube can pass directlyover the cell surface. A motorized stepper could re-position the tubessuch that the outflow from the second outlet tube flows over the cellallowing solution exchange at the cell membrane surface to occur within10-20 ms. Excess bath solution is removed via a tube positioned at theedge of the chamber connected to a vacuum line.

A prospective cell is positioned in the centre of the microscope fieldof view. Recording electrode is positioned directly above the cellmembrane surface. Using fine manipulator control (Luigs and Neumann,SM-6) the electrode is lowered, while monitoring the change in electroderesistance during delivery of a 5 mV depolarizing pulse, until a highresistance seal (gigaseal) is achieved. Whole cell configuration isachieved by removing by suction a small fragment of cell membraneimmediately beneath the recording electrode tip. The cell membranepotential is held at −70 mV (voltage-clamped) via the electrode(Axopatch 200B Integrating patch clamp amplifier, pClamp software, AxonInstruments). Test solutions are applied using the fast applicationsystem using the following protocol and changes in inward current arerecorded and stored for off-line analysis.

1) Control current—exchange from extracellular solution to extracellularsolution+30 μM AMPA (2 s application time, 30 s interval betweenapplications) repeated until measurements are stable.

2) Test current—exchange from extracellular solution+10 nM of compoundof invention to extracellular solution+10 nM of compound of invention+30μM AMPA (2 s application time, 30 s interval between applications)repeated until measurements are stable.

All experiments are performed at ambient temperature (20 to 22° C.).

The activity of a compound of the invention is determined by measuringthe area under the curve (during 2 s period of application) for the 30μM AMPA response in the presence of the compound of the invention andexpressing it as % of potentiation of the 30 μM AMPA alone response (30μM AMPA in the absence of the compound of the invention).

The range of mean responses at 10 nM increased 30 uM AMPA response by 14to 79% and at 10 uM by 42 to 679%.

1. A method of treating schizophrenia in a human comprisingadministering an therapeutically effective amount of1-[4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazoleor a salt thereof, alone or combined with a pharmaceutically acceptablecarrier, dilutent or excipient.
 2. The method of claim 1 comprisingcombining said compound or its salt with another antipsychotic drug. 3.A method of treating schizophrenia in a human comprising administeringan therapeutically effective amount of1-[4-(4-morpholinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazoleor a salt thereof, alone or combined with a pharmaceutically acceptablecarrier, dilutent or excipient.
 4. The method of claim 3 comprisingcombining said compound or its salt with another antipsychotic drug. 5.A method of treating impairment of cognition in a human comprisingadministering an therapeutically effective amount of1-[4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazoleor a salt thereof, alone or combined with a pharmaceutically acceptablecarrier, dilutent or excipient.
 6. A method of treating impairment ofcognition in a human comprising administering an therapeuticallyeffective amount of1-[4-(4-morpholinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazoleor a salt thereof, alone or combined with a pharmaceutically acceptablecarrier, dilutent or excipient.
 7. A pharmaceutical compositioncomprising1-[4-(1-pyrrolidinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazoleor a salt thereof, and a pharmaceutically acceptable carrier, dilutentor excipient.
 8. A pharmaceutical composition comprising1-[4-(4-morpholinylcarbonyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazoleor a salt thereof, and a pharmaceutically acceptable carrier, dilutentor excipient.